5-Substituted 2-aryl-4 pyrimidinones

ABSTRACT

Arylpyrimidinone compounds that act as selective modulators of CRF 1 receptors are provided. These compounds are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, and eating disorders. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds of the invention are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

The present application claims the benefit of U.S. provisionalapplication No. 60/219,703, filed Jul. 18, 2001, which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel arylpyrimidinone compounds thatbind with high selectivity and/or high affinity to CRF receptors(Corticotropin Releasing Factor Receptors). This invention also relatesto pharmaceutical compositions comprising such compounds and to the useof such compounds in treatment of psychiatric disorders and neurologicaldiseases, including major depression, anxiety-related disorders,post-traumatic stress disorder, supranuclear palsy and feedingdisorders, as well as treatment of immunological, cardiovascular orheart-related diseases and colonic hypersensitivity associated withpsychopathological disturbance and stress. Additionally this inventionrelates to the use such compounds as probes for the localization of CRFreceptors in cells and tissues. Preferred CRF receptors are CRF1receptors.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (CRF), a 41 amino acid peptide, is theprimary physiological regulator of proopiomelanocortin (POMC) derivedpeptide secretion from the anterior pituitary gland. In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain. There is alsoevidence that CRF plays a significant role in integrating the responseof the immune system to physiological, psychological, and immunologicalstressors.

Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system.

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals. Furthermore, the density of CRF receptors is significantlydecreased in the frontal cortex of suicide victims, consistent with ahypersecretion of CRF. In addition, there is a bluntedadrenocorticotropin (ACTH) response to CRF (i.v. administered) observedin depressed patients. Preclinical studies in rats and non-humanprimates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression. There is also preliminary evidence that tricyclicantidepressants can alter CRF levels and thus modulate the numbers ofCRF receptors in brain.

CRF has also been implicated in the etiology of anxiety-relateddisorders. CRF produces anxiogenic effects in animals and interactionsbetween benzodiazepine/non-benzodiazepine anxiolytics and CRF have beendemonstrated in a variety of behavioral anxiety models. Preliminarystudies using the putative CRF receptor antagonist ac-helical ovine CRF(9-41) in a variety of behavioral paradigms demonstrate that theantagonist produces “anxiolytic-like” effects that are qualitativelysimilar to the benzodiazepines. Neurochemical, endocrine and receptorbinding studies have all demonstrated interactions between CRF andbenzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test and in theacoustic startle test in rats. The benzodiazepine receptor antagonist Ro15-1788, which was without behavioral activity alone in the operantconflict test, reversed the effects of CRF in a dose-dependent manner,while the benzodiazepine inverse agonist FG 7142 enhanced the actions ofCRF.

CRF has also been implicated in the pathogeneisis of certainimmunological, cardiovascular or heart-related diseases such ashypertension, tachycardia and congestive heart failure, stroke andosteoporosis, as well as in premature birth, psychosocial dwarfism,stress-induced fever, ulcer, diarrhea, post-operative ileus and colonichypersensitivity associated with psychopathological disturbance andstress.

The mechanisms and sites of action through which conventionalanxiolytics and antidepressants produce their therapeutic effects remainto be fully elucidated. It has been hypothesized however, that they areinvolved in the suppression of CRF hypersecretion that is observed inthese disorders. Of particular interest are that preliminary studiesexamining the effects of a CRF receptor antagonist peptide (α-helicalCRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that theCRF antagonist produces “anxiolytic-like” effects qualitatively similarto the benzodiazepines.

DESCRIPTION OF THE RELATED ART

Certain small molecule compounds for the treatment of CRF relateddisorders have been disclosed in the literature (for a review see J.McCarthy et al. Current Pharmaceutical Design 1999, 5, 289 or P. J.Gilligan et al. Journal of Medicinal Chemistry 2000, 43, 1641).

McCarthy et al. (WO 96/39400) have disclosed aryl pyrimidine derivativesof the general formula

wherein X, R₁, R₂, R₃, and R₄ are defined therein, for use as CRFreceptor in the treatment of central nervous system disorders. TheMcCarthy application only discloses arylpyrimidine compounds thatcontain a disubstituted amino group (NR₁R₂) in the 4-position of thepyrimidine ring. It is therefore surprising that the novel pyrimidinonesof this invention, in which the disubstituted amino group is located onposition 5 of the central heterocyclic ring, and in which theheterocycle itself presents a carbonyl group on position 4 and asubstituent on the nitrogen atom on position 3, are also CRF receptorantagonists.

Murata et al. (WO 96/32383; U.S. Pat. No. 5,972,946) have disclosed thepreparation of certain compounds of the general formula

wherein R₅₁, R₆, R₇ and R₈ are defined therein, for use as syntheticintermediates in the preparation of acetamide derivatives of generalformula

for the treatment of certain diseases.

SUMMARY OF THE INVENTION

The invention provides novel compounds of Formula I (shown below), andpharmaceutical compositions comprising compounds of Formula I and atleast one pharmaceutically acceptable carrier or excipient. Theinvention also provides pharmaceutical manufacture, such as tablets,comprising a compound or pharmaceutically acceptable salt of Formula I.Such aryl pyrimidinone compounds bind to cell surface receptors,preferably G-coupled protein receptors, especially CRF receptors(including CRF 1 and CRF2 receptors) and most preferably CRF 1receptors. Preferred compounds of the invention exhibit high affinityfor CRF receptors, preferably CRF 1 receptors. Additionally, preferredcompounds of the invention also exhibit high specificity for CRFreceptors (i.e., they exhibit high selectivity compared to their bindingto non-CRF receptors). Preferably they exhibit high specificity for CRF1 receptors.

Thus, the invention is directed to compounds of Formula I

and the pharmaceutically acceptable salt thereof, wherein:

-   -   Ar is optionally substituted carbocyclic aryl or optionally        substituted heteroaryl, said heteroaryl having from 1 to 3        rings, and 5 to 7 ring members in each ring and, in at least one        of said rings, from 1 to about 3 heteroatoms selected from the        group consisting of N, O, and S;    -   R is oxygen, methyl, or absent;    -   R₁ is hydrogen, halogen, cyano, hydroxy, amino, cyano, nitro,        optionally substituted alkyl, optionally substituted alkenyl,        optionally substituted alkynyl, optionally substituted alkoxy,        optionally substituted mono- or di-alkylamino, optionally        substituted cycloalkyl, optionally substituted        (cycloalkyl)alkyl, optionally substituted alkylthio, optionally        substituted alkylsulfinyl, optionally substituted alkylsulfonyl,        or optionally substituted mono- or di-alkylcarboxamide;    -   R₂ is optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkynyl, optionally substituted        alkoxy, optionally substituted mono- or di-alkylamino,        optionally substituted cycloalkyl, optionally substituted        (cycloalkyl)alkyl, optionally substituted heterocycloalkyl,        optionally substituted alkyl ester, optionally substituted alkyl        ketone, optionally substituted alkylthio, optionally substituted        alkylsulfinyl, optionally substituted alkylsulfonyl, optionally        substituted mono- or di-alkylcarboxamide or optionally        substituted dialkylcarboxamide; and    -   R₃ is hydrogen, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, optionally        substituted alkoxy, optionally substituted mono- or        di-alkylamino, optionally substituted cycloalkyl, optionally        substituted (cycloalkyl)alkyl, optionally substituted alkyl        ester, optionally substituted alkyl ketone, optionally        substituted alkylthio, optionally substituted alkylsulfinyl,        optionally substituted alkylsulfonyl, or optionally substituted        mono- or di-alkylcarboxamide;    -   provided that R₁ is not hydrogen, alkyl, or trifluoromethyl when        R₂ is hydrogen, alkyl or alkenyl.

The invention further comprises methods of treating patients sufferingfrom certain disorders with a therapeutically effective amount of atleast one compound of the invention. These disorders include CNSdisorders, particularly affective disorders, anxiety disorders,stress-related disorders, eating disorders and substance abuse. Thepatient suffering from these disorders may be a human or other animal(preferably a mammal), such as a domesticated companion animal (pet) ora livestock animal. Preferred compounds of the invention for suchtherapeutic purposes are those that antagonize the binding of CRF to CRFreceptors (preferably CRF1, or less preferably CRF2 receptors). Theability of compounds to act as antagonists can be measured as an IC₅₀value as described below.

According to yet another aspect, the present invention providespharmaceutical compositions comprising compounds of Formula I or thepharmaceutically acceptable salts (by which term is also encompassedpharmaceutically acceptable solvates) thereof, which compositions areuseful for the treatment of the above-recited disorders. The inventionfurther provides methods of treating patients suffering from any of theabove-recited disorders with an effective amount of a compound orcomposition of the invention.

Additionally this invention relates to the use of the compounds of theinvention (particularly labeled compounds of this invention) as probesfor the localization of receptors in cells and tissues and as standardsand reagents for use in determining the receptor-binding characteristicsof test compounds.

Preferred arylpyrimdinone compounds of the invention exhibit goodactivity, i.e., a half-maximal inhibitory concentration (IC₅₀) of lessthan 1 millimolar, in the standard in vitro CRF receptor binding assayof Example 31, which follows. Particularly preferred 2,5-diarylpyrazinesof the invention exhibit an IC₅₀ of about 1 micromolar or less, stillmore preferably an IC₅₀ of about 100 nanomolar or less even morepreferably an IC₅₀ of about 10 nanomolar or less. Certain particularlypreferred compounds of the invention will exhibit an IC₅₀ of 1 nanomolaror less in such a defined standard in vitro CRF receptor binding assay.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of Formula I, described above, the invention isfurther directed to compounds and pharmaceutically acceptable salts ofFormula I (shown above) wherein:

-   -   Ar is chosen from phenyl optionally substituted with up to 5        groups R_(A), naphthyl optionally substituted with up to 5        groups R_(A), and heteroaryl optionally substituted with up to 5        groups R_(A), said heteroaryl having from 1 to 3 rings, 5 to 7        ring members in each ring and, in at least one of said rings,        from 1 to about 3 heteroatoms selected from the group consisting        of N, O, and S;    -   R is oxygen, methyl, or absent;    -   R₁ is chosen from hydrogen, halogen, hydroxy, cyano, nitro,        haloalkyl, haloalkoxy, alkyl, alkenyl, alkynyl, alkoxy,        cycloalkyl, (cycloalkyl)alkyl, mono- and di-aminoalkyl, and        —S(O),alkyl;    -   R₂ is XR_(C) or Y;    -   R₃ is chosen from hydrogen, haloalkyl, haloalkoxy, alkyl,        alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, mono-        and di-aminoalkyl, and —S(O)_(n)alkyl, XR_(C) and Y;    -   R_(A) is independently selected at each occurrence from halogen,        cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkyl        substituted with 0-2 R_(B), alkenyl substituted with 0-2 R_(B),        alkynyl substituted with 0-2 R_(B), cycloalkyl substituted with        0-2 R_(B), (cycloalkyl)alkyl substituted with 0-2 R_(B), alkoxy        substituted with 0-2 R_(B), —NH(alkyl) substituted with 0-2        R_(B), —N(alkyl)(alkyl) of which each alkyl is independently        substituted with 0-2 R_(B), —XR_(C), and Y;    -   R_(B) is independently selected at each occurrence from the        group consisting of halogen, hydroxy, cyano, amino, alkyl,        —O(alkyl), —NH(alkyl), —N(alkyl)(alkyl), —S(O)_(n)(alkyl),        haloalkyl, haloalkoxy, CO(alkyl), CONH(alkyl),        CON(alkyl)(alkyl), —XR_(C), and Y;    -   R_(C) and R_(D), which may be the same or different, are        independently selected at each occurrence from:        -   hydrogen, and        -   straight, branched, and cyclic alkyl groups, and            (cycloalkyl)alkyl groups, said straight, branched, and            cyclic alkyl groups, and (cycloalkyl)alkyl groups consist of            1 to 8 carbon atoms, and contain zero or one or more double            or triple bonds, each of which 1 to 8 carbon atoms may be            further substituted with one or more substituent(s)            independently selected from oxo, hydroxy, halogen, cyano,            amino, C₁-C₆alkoxy, —NH(C₁-C₆alkyl),            —N(C₁-C₆alkyl)(C₁-C₆alkyl), —NHC(═O)(C₁-C₆alkyl),            —N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), —NHS(O)_(n)(C₁-C₆alkyl),            —S(O)_(n)(C₁-C₆alkyl), —S(O)_(n)NH(C₁-C₆alkyl),            —S(O)_(n)N(C₁-C₆alkyl)(C₁-C₆alkyl), and Z;    -   X is independently selected at each occurrence from the group        consisting of —CH₂—, —CHR_(D)—, —O—, —C(═O)—, —C(═O)O—,        —S(O)_(n)—, —NH—, —NR_(D)—, —C(═O)NH—, —C(═O)NR_(D)—, —S(O),NH—,        —S(O)_(n)NR_(D)—, —OC(═S)S—, —NHC(═O)—, —NR_(D)C(═O)—,        —NHS(O)_(n)—, —OSiH₂—, —OSiH(C₁-C₄alkyl)-,        —OSi(C₁-C₄alkyl)(C₁-C₄alkyl)-, and —NR_(D)S(O)_(n)—;    -   Y and Z are independently selected at each occurrence from: 3-        to 7-membered carbocyclic or heterocyclic groups which are        saturated, unsaturated, or aromatic, which may be further        substituted with one or more substituents independently selected        from halogen, oxo, hydroxy, amino, cyano, alkyl, —O(alkyl),        —NH(alkyl), —N(alkyl)(alkyl), and —S(O)_(n)(alkyl),        -   wherein said 3- to 7-memberered heterocyclic groups contain            one or more heteroatom(s) independently selected from N, O,            and S, with the point of attachment being either carbon or            nitrogen; and    -   n is independently selected at each occurrence from 0, 1, and 2;    -   provided that R₁ is not hydrogen, alkyl, or trifluoromethyl when        R₂ is hydrogen, alkyl or alkenyl. Such compounds will be        referred to as compounds of Formula IA.

Preferred compounds and salts of Formula I

-   -   Ar and R are as for Formula IA;    -   R₁ is chosen from hydrogen, halogen, hydroxy, cyano, nitro,        halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆alkyl, C₂-C₆alkenyl,        C₂-C₆alkynyl, C₁-C₆alkoxy, C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl)        C₁-C₄alkyl, mono- and di-amino(C₁-C₆)alkyl, and        -   —S(O)_(n)(C₁-C₆)alkyl;    -   R₂ is XR_(C) or Y;    -   R₃ is chosen from hydrogen, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy,        C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl) C₁-C₄alkyl, mono- and        di-amino(C₁-C₄)alkyl, and —S(O)_(n)(C₁-C₆)alkyl, XR_(C) and Y;    -   R_(A) is independently selected at each occurrence from halogen,        cyano, nitro, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy,        amino, C₁-C₆alkyl substituted with 0-2 R_(B), C₂-C₆alkenyl        substituted with 0-2 R_(B), C₂-C₆alkynyl substituted with 0-2        R_(B), C₃-C₇Cycloalkyl substituted with 0-2 R_(B),        (C₃-C₇Cycloalkyl) C₁-C₄alkyl substituted with 0-2 R_(B),        -   C₁-C₆alkoxy substituted with 0-2 R_(B), —NH(C₁-C₆alkyl)            substituted with 0-2 R_(B),        -   —N(C₁-C₆alkyl)(C₁-C₆alkyl) of which each C₁-C₆alkyl is            independently substituted with 0-2 R_(B), —XR_(C), and Y;    -   R_(B) is independently selected at each occurrence from the        group consisting of:    -   i) halogen, hydroxy, cyano, amino, C₁-C₄alkyl, —O(C₁-C₄alkyl),        —NH(C₁-C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl), —S(O)_(n)(alkyl),        halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, CO(C₁-C₄alkyl),        CONH(C₁-C₄alkyl), CON(C₁-C₄alkyl)(C₁-C₄alkyl), —XR_(C), and    -   ii) morpholino, pyrrolidino, piperidino, thiomorpholino, and        piperazino, each of which is optionally substituted with up to        three substituents independently chosen from hydroxy, halogen,        alkyl and alkoxy;    -   R_(C) and R_(D), which may be the same or different, are        independently selected at each occurrence from:        -   hydrogen, and        -   straight, branched, and cyclic alkyl groups, and            (cycloalkyl)alkyl groups, said straight, branched, and            cyclic alkyl groups, and (cycloalkyl)alkyl groups consist of            1 to 8 carbon atoms, and contain zero or one or more double            or triple bonds, each of which 1 to 8 carbon atoms may be            further substituted with one or more substituent(s)            independently selected from oxo, hydroxy, halogen, cyano,            amino, C₁-C₆alkoxy, —NH(C₁-C₆alkyl),            —N(C₁-C₆alkyl)(C₁-C₆alkyl), —NHC(═O)(C₁-C₆alkyl),            —N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), —NHS(O)_(n)(C₁-C₆alkyl),            —S(O)_(n)(C₁-C₆alkyl), —S(O)_(n)NH(C₁-C₆alkyl),        -   —S(O)_(n)N(C₁-C₆alkyl)(C₁-C₆alkyl), and Z;    -   X is independently selected at each occurrence from the group        consisting of —CH₂—, —CHR_(D)—, —O—, —C(═O)—, —C(═O)O—,        —S(O)_(n)—, —NH—, —NR_(D)—, —C(═O)NH—, —C(═O)NR_(D)—,        —S(O)_(n)NH—, —S(O)_(n)NR_(D)—, —OC(═S)S—, —NHC(═O)—,        —NR_(D)C(═O)—, —NHS(O)_(n)—, —OSiH₂—, —OSiH(C₁-C₄alkyl)-,        —OSi(C₁-C₄alkyl)(C₁-C₄alkyl)-, and —NR_(D)S(O)_(n)—;    -   Y and Z are independently selected at each occurrence from: 3-        to 7-membered carbocyclic or heterocyclic groups which are        saturated, unsaturated, or aromatic, which may be further        substituted with one or more substituents independently selected        from halogen, oxo, hydroxy, amino, cyano, C₁-C₄alkyl,        —O(C₁-C₄alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl),and        —S(O)_(n)(alkyl),        -   wherein said 3- to 7-memberered heterocyclic groups contain            one or more heteroatom(s) independently selected from N, O,            and S, with the point of attachment being either carbon or            nitrogen; and    -   n is independently selected at each occurrence from 0, 1, and 2;    -   provided that R₁ is not hydrogen, alkyl, or trifluoromethyl when        R₂ is hydrogen, alkyl or alkenyl,    -   provided that R₁ is not hydrogen, alkyl, or trifluoromethyl when        R₂ is hydrogen, alkyl or alkenyl. Such compounds will be        referred to as compounds of Formula IB.

Also provided by the invention are compounds and salts of Formula IA andIB, wherein

-   -   R is absent;    -   Ar is chosen from phenyl, naphthyl, pyridyl, pyrimidinyl,        pyrazinyl, pyridizinyl, thienyl, thiazolyl, oxazolyl,        isoxazolyl, pyrrolyl, furanyl, and triazolyl, each of which is        optionally substituted with up to 5 independently chosen groups        R_(A), wherein at least one position of said phenyl that is        ortho or para to the point of attachment of Ar in Formula I is        substituted.

More preferably Ar is chosen from phenyl, naphthyl, or pyridyl each ofwhich is substituted with from 1 to 5 independently chosen groups R_(A),wherein at least one position of Ar that is ortho or para to the pointof attachment of Ar in Formula I is substituted.

Most preferably Ar is phenyl which is substituted with from 1 to 5independently chosen groups R_(A), wherein at least one position of Arthat is ortho or para to the point of attachment of Ar in Formula I issubstituted.

Other preferred compounds and salts of Formula IA and Formula IB arethose wherein:

-   -   R is absent;    -   Ar is phenyl substituted with from 1 to 5 independently chosen        groups R_(A), wherein at least one position of Ar that is ortho        or para to the point of attachment of Ar in Formula I is        substituted;    -   R₁ is selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and    -   R₃ is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆alkoxy,        halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,        (C₃-C₇cycloalkyl)C₁-C₄alkyl, pyrrolidin-1-yl(C₁-C₄)alkyl,        piperidin-1-yl(C₁-C₄)alkyl, piperazin-1-yl(C₁-C₄)alkyl,        morpholin-4-yl(C₁-C₄)alkyl, and thiomorpholin-4-yl(C₁-C₄)alkyl.

Also included in the invention are compounds and salts of Formula IA andIB wherein

-   -   R is absent;    -   Ar is phenyl substituted with from 1 to 5 independently chosen        groups R_(A), wherein at least one position of Ar that is ortho        or para to the point of attachment of Ar in Formula I is        substituted; and    -   R_(C) and R_(D), which may be the same or different, are        independently selected at each occurrence from:        -   hydrogen, and straight, branched, and cyclic alkyl groups,            and (cycloalkyl)alkyl groups, said straight, branched, and            cyclic alkyl groups, and (cycloalkyl)alkyl groups consist of            1 to 8 carbon atoms, and contain zero or one or more double            or triple bonds.

Further provided by the invention are compounds and salts of Formula IAand Formula IB wherein:

-   -   R is absent;    -   Ar is phenyl substituted with from 1 to 5 independently chosen        groups R_(A), wherein at least one position of Ar that is ortho        or para to the point of attachment of Ar in Formula I is        substituted;    -   R₁ is selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy;    -   R₃ is selected from hydrogen, halogen, C₁-C₆alkyl, C₁-C₆alkoxy,        halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,        (C₃-C₇cycloalkyl)C₁-C₄alkyl, pyrrolidino-1-yl(C₁-C₄)alkyl,        piperidin-1-yl(C₁-C₄)alkyl, piperazin-1-yl(C₁-C₄)alkyl,        morpholin-4-yl(C₁-C₄)alkyl, and thiomorpholin-4-yl(C₁-C₄)alkyl;        and    -   R_(C) and R_(D), which may be the same or different, are        independently selected at each occurrence from:        -   hydrogen, and straight, branched, and cyclic alkyl groups,            and (cycloalkyl)alkyl groups, said straight, branched, and            cyclic alkyl groups, and (cycloalkyl)alkyl groups consist of            1 to 8 carbon atoms, and contain zero or one or more double            or triple bonds.

Other preferred R₂ groups for compounds of Formula IA and Formula IB aregroups of the formula

and groups of the formula

where A represents up to three groups independently chosen fromhydrogen, halogen, alkyl, and alkoxy.

The invention further provides compounds and salts of Formula II,Formula III, Formula IV wherein

wherein:

-   -   R_(X) and R_(Y) are independently chosen from hydrogen,        C₁-C₆alkyl₁,    -   (C₃-C₇cycloalkyl₂)C₁-C₄alkyll, and mono- and        di(C₁-C₆)alkyliamino;        -   where each alkyll is independently straight, branched, or            cyclic, contains zero or 1 or more double or triple bonds,            and is optionally substituted with one or more substituents            independently chosen from halogen, hydroxy, amino, oxo,            cyano, C₁-C₄alkoxy, and mono- and di(C₁-C₄)alkylamino,    -   where each C₃-C₇cycloalkyl₂ is optionally substituted by one or        more substituents independently chosen from halogen, amino,        hydroxy, oxo, cyano, C₁-C₄alkoxy, and mono- or        di(C₁-C₄)alkylamino;    -   R₁, R₃ and Ar are as defined Formula IA or Formula IB;    -   and for Formula IV,    -   R₄ represents up to three substituents independently chosen from        hydrogen, halogen, C₁-C₆alkyl, and C₁-C₆ alkoxy; and    -   q is 0, 1, or 2.

More preferred compounds and salts of Formula II, Formula III, andFormula IV are those wherein

-   -   Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl,        pyridizinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl,        furanyl, and triazolyl, each of which is optionally substituted        with up to 5 independently chosen groups R_(A), where R_(A) is        as defined for Formula IA or more preferably as defined for        compounds of Formula IB and wherein at least one position of        said phenyl that is ortho or para to the point of attachment of        Ar in Formula IA or IB is substituted.

More preferably Ar is chosen from phenyl, naphthyl, and pyridyl (wherephenyl is particularly preferred), each of which is substituted withfrom 1 to 5 independently chosen groups R_(A), wherein at least oneposition of Ar that is ortho or para to the point of attachment of Ar inFormula II, Formula III, or Formula IV is substituted; and for FormulaIV,

-   -   R₄ represents up to three substituents independently chosen from        hydrogen, halogen, C₁-C₆alkyl, and C₁-C₆ alkoxy; and    -   q is 0, 1, or 2.

Other preferred compounds and salts of Formula II, Formula III andFormula IV include those wherein:

-   -   Ar is phenyl substituted with from 1 to 5 independently chosen        groups R_(A), wherein at least one position of Ar that is ortho        or para to the point of attachment of Ar in Formula II, Formula        III and Formula IV is substituted;    -   R₁ is selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        halo(C₁-C₂)alkyl, and        -   halo(C₁-C₂)alkoxy;    -   R₃ is selected from hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy,        halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,        (C₃-C₇cycloalkyl)C₁-C₄alkyl, pyrrolidin-1-yl(C₁-C₄)alkyl,        piperidin-1-yl(C₁-C₄)alkyl, piperazin-1-yl(C₁-C₄)alkyl,        morpholin-4-yl(C₁-C₄)alkyl, and thiomorpholin-4-yl(C₁-C₄)alkyl;    -   and for Formula IV,    -   R₄ represents up to three substituents independently chosen from        hydrogen, halogen, C₁-C₆alkyl, and C₁-C₆ alkoxy; and    -   q is 0, 1, or 2.

Additional embodiments of the invention include compounds and salts ofFormula II, Formula III, and Formula IV, wherein

-   -   Ar is phenyl substituted with from I to 5 independently chosen        groups R_(A), wherein at least one position of Ar that is ortho        or para to the point of attachment of Ar in Formula II, Formula        III and Formula IV is substituted;    -   R₁ is selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        halo(C₁-C₂)alkyl, and        -   halo(C₁-C₂)alkoxy; and    -   R₃ is selected from hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy,        halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,        (C₃-C₇cycloalkyl)C₁-C₄alkyl, pyrrolidino-1-yl(C₁-C₄)alkyl,        piperidin-1-yl(C₁-C₄)alkyl, piperazin-1-yl(C₁-C₄)alkyl,        morpholin-4-yl(C₁-C₄)alkyl, and thiomorpholinA4-yl(C₁-C₄)alkyl;        and    -   R_(C) and R_(D), which may be the same or different, are        independently selected at each occurrence from:        -   hydrogen, and straight, branched, and cyclic alkyl groups,            and (cycloalkyl)alkyl groups, said straight, branched, and            cyclic alkyl groups, and (cycloalkyl)alkyl groups consist of            1 to 8 carbon atoms, and contain zero or one or more double            or triple bonds;    -   and for Formula IV,    -   R₄ represents up to three substituents independently chosen from        hydrogen, halogen, C₁-C₆alkyl, and C₁-C₆ alkoxy; and    -   q is 0, 1, or 2.

The invention is particularly directed to compounds and salts of FormulaII, Formula III and Formula IV wherein

-   -   Ar is phenyl substituted with from 1 to 3 substituents        independently chosen from:        -   halogen, cyano, nitro, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,            hydroxy, amino, C₃-C₇ cycloalkyl, (C₃-C₇cycloalkyl)            (C₁-C₄)alkyl, C₁-C₆alkyl substituted with 0-2 R_(B),            C₁-C₆alkoxy substituted with 0-2 R_(B), —NH(C₁-C₄alkyl)            substituted with 0-2 R_(B), —N(C₁-C₄alkyl)( C₁-C₄alkyl) of            which each C₁-C₄alkyl is independently substituted with 0-2            R_(B),        -   wherein at least one position of Ar that is ortho or para to            the point of attachment of Ar in Formula II, Formula III and            Formula IV is substituted;    -   R_(B) is independently selected at each occurrence from the        group consisting of:    -   i) halogen, hydroxy, amino, C₁-C₄alkyl, —O(C₁-C₄alkyl),        —NH(C₁-C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl), and    -   ii) morpholino, pyrrolidino, piperidino, thiomorpholino, and        piperazino;    -   R₁ is selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,        halo(C₁-C₂)alkyl, and        -   halo(C₁-C₂)alkoxy;    -   R₃ is selected from hydrogen, C₁-C₆alkyl, C₁-C₆alkoxy,        halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,        (C₃-C₇cycloalkyl)C₁-C₄alkyl, pyrrolidin-1-yl(C₁-C₄)alkyl,        piperidin-1-yl(C₁-C₄)alkyl, piperazin-1-yl(C₁-C₄)alkyl,        morpholin-4-yl(C₁-C₄)alkyl, and thiomorpholin-4-yl(C₁-C₄)alkyl;    -   and for Formula IV,    -   R₄ represents up to three substituents independently chosen from        hydrogen, halogen, C₁-C₆alkyl, and C₁-C₆ alkoxy; and    -   q is 0, 1, or 2.

Particularly preferred compounds and salts of Formula II, Formula III,and Formula IV are those wherein:

-   -   Ar is phenyl substituted with from 1 to 3 substituents        independently chosen from:        -   halogen, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, hydroxy,            amino, C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl) C₁-C₄alkyl, mono            and di(C₁-C₄)alkylamino, C₁-C₆alkyl substituted with        -   0-2 R_(B), C₁-C₆alkoxy substituted with 0-2 R_(B),        -   wherein at least one position of Ar that is ortho or para to            the point of attachment of Ar in Formula II, Formula III and            Formula IV is substituted;    -   R_(B) is independently selected at each occurrence from the        group consisting of:    -   i) halogen, hydroxy, amino, C₁-C₄alkyl, —O(C₁-C₄alkyl),        —NH(C₁-C₄alkyl), —N(C₁-C_(C) ₄alkyl)(C₁-C₄alkyl), and    -   ii) morpholino, pyrrolidino, piperidino, thiomorpholino, and        piperazino;    -   R₁ is selected from hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy,        halo(C₁-C₂)alkyl, and        -   halo(C₁-C₂)alkoxy; and    -   R₃ is selected from hydrogen, C₁-C₄alkyl, C₁-C₄alkoxy,        halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy,        (C₃-C₇cycloalkyl)C₁-C₄alkyl, pyrrolidin-1-yl(C₁-C₄)alkyl,        piperidin-1-yl(C₁-C₄)alkyl, piperazin-1-yl(C₁-C₄)alkyl,        morpholin-4-yl(C₁-C₄)alkyl, and thiomorpholin-4-yl(C₁-C₄)alkyl;        and for Formula IV,    -   R₄ represents up to three substituents independently chosen from        hydrogen, halogen, C₁-C6alkyl, and C₁-C₆ alkoxy; and    -   q is 0, 1, or 2.

Additionally, the invention provides compounds of Formula II and FormulaIII wherein

-   -   R_(X) and R_(Y) are the same or different and are independently        selected from hydrogen or straight, branched or cyclic alkyl        groups, optionally containing one or more aza or oxa bridge, and        optionally containing one or more double or triple bonds; and    -   R₁, R₃ and Ar are as defined Formula IA or Formula IB.

Further provided by the invention are compounds and salts of FormulaV-Formula IX

wherein

-   -   Ar is phenyl substituted with from 1 to 3 substituents        independently chosen from:

halogen, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, hydroxy, amino,C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl) C₁-C₄alkyl, mono anddi(C₁-C₄)alkylamino, C₁-C₆alkyl substituted with

-   -   -   0-2 R_(B), C₁-C₆alkoxy substituted with 0-2 R_(B),        -   wherein at least one position of Ar that is ortho or para to            the point of attachment of Ar in Formula V-Formula IX is            substituted;

    -   R_(B) is independently selected at each occurrence from the        group consisting of:

    -   i) halogen, hydroxy, amino, C₁-C₄alkyl, —O(C₁-C₄alkyl),        —NH(C₁-C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl), and

    -   ii) morpholino, pyrrolidino, piperidino, thiomorpholino, and        piperazino;

    -   R₁ is selected from hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy,        halo(C₁-C₂)alkyl, and        -   halo(C₁-C₂)alkoxy; and

    -   R₃ is selected from hydrogen, C₁-C₄alkyl, C₁-C₄alkoxy,        halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy,        (C₃-C₇cycloalkyl)C₁-C₄alkyl, pyrrolidin-1-yl(C₁-C₄)alkyl,        piperidin-1-yl(C₁-C₄)alkyl, piperazin-1-yl(C₁-C₄)alkyl,        morpholin-4-yl(C₁-C_(C) ₄)alkyl, and        thiomorpholin-4-yl(C₁-C₄)alkyl.

Compounds of the invention are useful in treating a variety ofconditions including affective disorders, anxiety disorders, stressdisorders, eating disorders, and drug addiction.

Affective disorders include all types of depression, bipolar disorder,cyclothymia, and dysthymia.

Anxiety disorders include generalized anxiety disorder, panic, phobiasand obsessive-compulsive disorder.

Stress-related disorders include post-traumatic stress disorder,hemorrhagic stress, stress-induced psychotic episodes, psychosocialdwarfism, stress headaches, stress-induced immune systems disorders suchas stress-induced fever, and stress-related sleep disorders.

Eating disorders include anorexia nervosa, bulimia nervosa, and obesity.

Modulators of the CRF receptors are also useful in the treatment (e.g.,symptomatic treatment)of a variety of neurological disorders includingsupranuclear palsy, AIDS related dementias, multiinfarct dementia,neurodegenerative disorders such as Alzheimer's disease, Parkinson'sdisease, and Huntington's disease, head trauma, spinal cord trauma,ischemic neuronal damage, amyotrophic lateral sclerosis, disorders ofpain perception such as fibromyalgia and epilepsy.

Additionally compounds of Formula I are useful as modulators of the CRFreceptor in the treatment (e.g., symptomatic treatment) of a number ofgastrointestinal, cardiovascular, hormonal, autoimmune and inflammatoryconditions. Such conditions include irritable bowel syndrome, ulcers,Crohn's disease, spastic colon, diarrhea, post operative ilius andcolonic hypersensitivity associated with psychopathological disturbancesor stress, hypertension, tachycardia, congestive heart failure,infertility, euthyroid sick syndrome, inflammatory conditions effectedby rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis andallergies.

Compounds of Formula I are also useful as modulators of the CRF1receptor in the treatment of animal disorders associated with aberrantCRF levels. These conditions include porcine stress syndrome, bovineshipping fever, equine paroxysmal fibrillation, and dysfunctions inducedby confinement in chickens, sheering stress in sheep or human-animalinteraction related stress in dogs, psychosocial dwarfism andhypoglycemia.

Typical subjects to which compounds of the invention may be administeredwill be mammals, particularly primates, especially humans. Forveterinary applications, a wide variety of subjects will be suitable,e.g. livestock such as cattle, sheep, goats, cows, swine and the like;poultry such as chickens, ducks, geese, turkeys, and the like; and otherdomesticated animals particularly pets such as dogs and cats. Fordiagnostic or research applications, a wide variety of mammals will besuitable subjects including rodents (e.g. mice, rats, hamsters),rabbits, primates, and swine such as inbred pigs and the like.Additionally, for in vitro applications, such as in vitro diagnostic andresearch applications, body fluids (e.g., blood, plasma, serum, CSF,lymph, cellular interstitial fluid, aqueous humor, saliva, synovialfluid, feces, or urine) and cell and tissue samples of the abovesubjects will be suitable for use.

The CRF binding compounds provided by this invention and labeledderivatives thereof are also useful as standards and reagents indetermining the ability of test compounds (e.g., a potentialpharmaceutical) to bind to a CRF receptor.

Labeled derivatives the CRF antagonist compounds provided by thisinvention are also useful as radiotracers for positron emissiontomography (PET) imaging or for single photon emission computerizedtomography (SPECT).

More particularly compounds of the invention may be used fordemonstrating the presence of CRF receptors in cell or tissue samples.This may be done by preparing a plurality of matched cell or tissuesamples, at least one of which is prepared as an experiment sample andat least one of which is prepared as a control sample. The experimentalsample is prepared by contacting (under conditions that permit bindingof CRF to CRF receptors within cell and tissue samples) at least one ofthe matched cell or tissue samples that has not previously beencontacted with any compound or salt of the invention with anexperimental solution comprising the detectably-labeled preparation ofthe selected compound or salt at a first measured molar concentration.The control sample is prepared by in the same manner as the experimentalsample and is incubated in a solution that contains the same ingredientsas the experimental solution but that also contains an unlabelledpreparation of the same compound or salt of the invention at a molarconcentration that is greater than the first measured molarconcentration.

The experimental and control samples are then washed to remove unbounddetectably-labeled compound. The amount of detectably-labeled compoundremaining bound to each sample is then measured and the amount ofdetectably-labeled compound in the experimental and control samples iscompared. A comparison that indicates the detection of a greater amountof detectable label in the at least one washed experimental sample thanis detected in any of the at least one washed control samplesdemonstrates the presence of CRF receptors in that experimental sample.

The detectably-labeled compound used in this procedure may be labeledwith any detectable label, such as a radioactive label, a biological tagsuch as biotin (which can be detected by binding to detectably-labeledavidin), an enzyme (e.g., alkaline phosphatase, beta galactosidase, or alike enzyme that can be detected its activity in a colorimetric assay)or a directly or indirectly luminescent label. When tissue sections areused in this procedure and the detectably-labeled compound isradiolabeled, the bound, labeled compound may be detectedautoradiographically to generate an autoradiogram. When autoradiographyis used, the amount of detectable label in an experimental or controlsample may be measured by viewing the autoradiograms and comparing theexposure density of the autoradiograms.

The present invention also pertains to methods of inhibiting the bindingof CRF to CRF receptors (preferably CFR₁ receptors) which methodsinvolve contacting a solution containing a CRF antagonist compound ofthe invention with cells expressing CRF receptors, wherein the compoundis present in the solution at a concentration sufficient to inhibit CRFbinding to CRF receptors in vitro. This method includes inhibiting thebinding of CRF to CRF receptors in vivo, e.g., in a patient given anamount of a compound of Formula I that would be sufficient to inhibitthe binding of CRF to CRF receptors in vitro. In one embodiment, suchmethods are useful in treating physiological disorders associated withexcess concentrations of CRF. The amount of a compound that would besufficient to inhibit the binding of a CRF to the CRF receptor may bereadily determined via a CRF receptor binding assay (see, e.g., Example31), or from the EC₅o of a CRF receptor functional assay, such as astandard assay of CRF receptor mediated chemotaxis. The CRF receptorsused to determine in vitro binding may be obtained from a variety ofsources, for example from cells that naturally express CRF receptors,e.g. IMR32 cells or from cells expressing cloned human CRF receptors.

The present invention also pertains to methods for altering the activityof CRF receptors, said method comprising exposing cells expressing suchreceptors to an effective amount of a compound of the invention, whereinthe compound is present in the solution at a concentration sufficient tospecifically alter the signal transduction activity in response to CRFin cells expressing CRF receptors in vitro, preferred cells for thispurpose are those that express high levels of CRF receptors (i.e., equalto or greater than the number of CRF1 receptors per cell found indifferentiated IMR-32 human neuroblastoma cells), with IMR-32 cellsbeing particularly preferred for testing the concentration of a compoundrequired to alter the activity of CRF1 receptors. This method includesaltering the signal transduction activity of CRF receptors in vivo,e.g., in a patient given an amount of a compound of Formula I that wouldbe sufficient to alter the signal transduction activity in response toCRF in cells expressing CRF receptors in vitro. The amount of a compoundthat would be sufficient to alter the signal transduction activity inresponse to CRF of CRF receptors may also be determined via an assay ofCRF receptor mediated signal transduction, such as an assay wherein thebinding of CRF to a cell surface CRF receptor effects a changes inreporter gene expression.

The present invention also pertains to packaged pharmaceuticalcompositions for treating disorders responsive to CRF receptormodulation, e.g., eating disorders, depression or stress. The packagedpharmaceutical compositions include a container holding atherapeutically effective amount of at least one CRF 1 receptormodulator as described supra and instructions for using the treatingdisorder responsive to CRF1 receptor modulation in the patient.

Chemical Description and Terminology

The compounds herein described may have one or more asymmetric centersor planes. Compounds of the present invention containing anasymmetrically substituted atom may be isolated in optically active orracemic forms. It is well known in the art how to prepare opticallyactive forms, such as by resolution of racemic forms (racemates), byasymmetric synthesis, or by synthesis from optically active startingmaterials. Resolution of the racemates can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiral HPLCcolumn. Many geometric isomers of olefins, C═N double bonds, and thelike can also be present in the compounds described herein, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral (enantiomeric and diastereomeric), andracemic forms, as well as all geometric isomeric forms of a structureare intended, unless the specific stereochemistry or isomeric form isspecifically indicated.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-2 R*, then said group mayoptionally be substituted with up to two R* groups and R* at eachoccurrence is selected independently from the definition of R*. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Formula I includes, but is not limited to, compounds of Formula IA,Formula IB, and Formula II-Formula IX.

As indicated above, various substituents of the various formulae(compounds of Formula I, IA, IB, II, etc.) are “optionally substituted”,including arylpyrimidinone compounds of Formula I and subformulaethereof, and such substituents as recited in the sub-formulae such asFormula I and subformulae. The term “substituted,” as used herein, meansthat any one or more hydrogens on the designated atom or group isreplaced with a selection from the indicated group of substituents,provided that the designated atom's normal valence is not exceeded, andthat the substitution results in a stable compound. When a substituentis oxo (keto, i.e., ═O), then 2 hydrogens on an atom are replaced. Thepresent invention is intended to include all isotopes (includingradioisotopes) of atoms occurring in the present compounds.

When substituents such as Ar, R₁, R₂, and R₃ are further substituted,they may be so substituted at one or more available positions, typically1 to 3 or 4 positions, by one or more suitable groups such as thosedisclosed herein. Suitable groups that may be present on a “substituted”Ar, R₁, R₂, and R₃ or other group include e.g., halogen; cyano;hydroxyl; nitro; azido; alkanoyl (such as a C₁-C₆ alkanoyl group such asacyl or the like); carboxamido; alkyl groups (including cycloalkylgroups, having 1 to about 8 carbon atoms, preferably 1, 2, 3, 4, 5, or 6carbon atoms); alkenyl and alkynyl groups (including groups having oneor more unsaturated linkages and from 2 to about 8, preferably 2, 3, 4,5 or 6, carbon atoms); alkoxy groups having one or more oxygen linkagesand from 1 to about 8, preferably 1, 2, 3, 4, 5 or 6 carbon atoms;aryloxy such as phenoxy; alkylthio groups including those having one ormore thioether linkages and from 1 to about 8 carbon atoms, preferably1, 2, 3, 4, 5 or 6 carbon atoms; alkylsulfinyl groups including thosehaving one or more sulfinyl linkages and from 1 to about 8 carbon atoms,preferably 1, 2, 3, 4, 5, or 6 carbon atoms; alkylsulfonyl groupsincluding those having one or more sulfonyl linkages and from 1 to about8 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms; aminoalkylgroups including groups having one or more N atoms and from 1 to about8, preferably 1, 2, 3, 4, 5 or 6, carbon atoms; carbocyclic aryl having6 or more carbons and one or more rings, (e.g., phenyl, biphenyl,naphthyl, or the like, each ring either substituted or unsubstitutedaromatic); arylalkyl having 1 to 3 separate or fused rings and from 6 toabout 18 ring carbon atoms, with benzyl being a preferred arylalkylgroup; arylalkoxy having 1 to 3 separate or fused rings and from 6 toabout 18 ring carbon atoms, with O-benzyl being a preferred arylalkoxygroup; or a saturated, unsaturated, or aromatic heterocyclic grouphaving 1 to 3 separate or fused rings with 3 to about 8 members per ringand one or more N, O or S atoms, e.g. coumarinyl, quinolinyl,isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidyl, furanyl,pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl,imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such heterocyclic groups may be further substituted, e.g.with hydroxy, alkyl, alkoxy, halogen and amino.

As used herein, the term “aryl” includes groups that contain 1 to 3separate or fused rings and from 6 to about 18 ring atoms, withouthetero atoms as ring members. Specifically preferred carbocyclic arylgroups include phenyl, and naphthyl including 1-napthyl and 2-naphthyl.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, having thespecified number of carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl,t-butyl, n-pentyl, and s-pentyl. Preferred alkyl groups are C₁-C₁₀ alkylgroups. Especially preferred alkyl groups are methyl, ethyl, propyl,butyl, and 3-pentyl. The term C,₄ alkyl as used herein includes alkylgroups consisting of 1 to 4 carbon atoms, which may contain acyclopropyl moiety. Suitable examples are methyl, ethyl, andcyclopropylmethyl.

“Cycloalkyl” is intended to include saturated ring groups, having thespecified number of carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. Cycloalkyl groups typically will have 3 toabout 8 ring members.

In the term “(C₃-C₇cycloalkyl)C₁-C₄alkyl”, cycloalkyl, and alkyl are asdefined above, and the point of attachment is on the alkyl group. Thisterm encompasses, but is not limited to, cyclopropylmethyl,cyclohexylmethyl, and cyclohexylmethyl. “Alkenyl” is intended to includehydrocarbon chains of either a straight or branched configurationcomprising one or more unsaturated carbon-carbon bonds, which may occurin any stable point along the chain, such as ethenyl and propenyl.Alkenyl groups typically will have 2 to about 8 carbon atoms, moretypically 2 to about 6 carbon atoms.

“Alkynyl” is intended to include hydrocarbon chains of either a straightor branched configuration comprising one or more carbon-carbon triplebonds, which may occur in any stable point along the chain, such asethynyl and propynyl. Alkynyl groups typically will have 2 to about 8carbon atoms, more typically 2 to about 6 carbon atoms.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen atoms. Preferredexamples of haloalkyl include, but are not limited to, mono-, di-, ortri-fluoromethyl, mono-, di-, or tri-chloromethyl, mono-, di-, tri-,tetra-, or penta-fluoroethyl, and mono-, di-, tri-, tetra-, orpenta-chloroethyl. Typical haloalkyl groups will have 1 to about 8carbon atoms, more typically 1 to about 6 carbon atoms.

“Alkoxy” represents an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge. Examples ofalkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy. Alkoxy groups typically have 1 to about 8 carbon atoms,more typically 1 to about 6 carbon atoms.

“Halolkoxy” represents a haloalkyl group as defined above with theindicated number of carbon atoms attached through an oxygen bridge.Preferred examples of haloalkoxy groups include trifluoromethoxy,2-fluoroethoxy, and difluromethoxy.

As used herein, the term “alkylthio” includes those groups having one ormore thioether linkages and preferably from I to about 8 carbon atoms,more typically 1 to about 6 carbon atoms.

As used herein, the term “alkylsulfinyl” includes those groups havingone or more sulfoxide (SO) linkage groups and typically from 1 to about8 carbon atoms, more typically 1 to about 6 carbon atoms.

As used herein, the term “alkylsulfonyl” includes those groups havingone or more sulfonyl (SO₂) linkage groups and typically from 1 to about8 carbon atoms, more typically 1 to about 6 carbon atoms.

As used herein, the term “alkylamino” includes those groups having oneor more primary, secondary and/or tertiary amine groups and typicallyfrom 1 to about 8 carbon atoms, more typically 1 to about 6 carbonatoms.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, oriodo; and “counter-ion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As used herein, “carbocyclic group” is intended to mean any stable 3- to7-membered monocyclic or bicyclic or 7-to 13-membered bicyclic ortricyclic group, any of which may be saturated, partially unsaturated,or aromatic. In addition to those exemplified elsewhere herein, examplesof such carbocycles include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2:2.2]bicyclooctanyl, fluorenyl, phenyl, naphthyl, indanyl, andtetrahydronaphthyl.

As used herein, the term “heterocyclic group” is intended to includesaturated, partially unsaturated, or unsaturated (aromatic) groupshaving 1 to 3 (preferably fused) rings with 3 to about 8 members perring at least one ring containing an atom selected from N, O or S. Thenitrogen and sulfur heteroatoms may optionally be oxidized. The term or“heterocycloalkyl” is used to refer to saturated heterocyclic groups.

The heterocyclic ring may be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. A nitrogen in theheterocycle may optionally be quaternized. As used herein, the term“aromatic heterocyclic system” is intended to include any stable 5- to7-membered monocyclic or 10- to 14-membered bicyclic heterocyclicaromatic ring system which comprises carbon atoms and from 1 to 4heteroatoms independently selected from the group consisting of N, O andS. It is preferred that the total number of S and O atoms in thearomatic heterocycle is not more than 2, more preferably not more than1.

Examples of heterocycles include, but are not limited to, thoseexemplified elsewhere herein and further include acridinyl, azocinyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl,thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

Preferred heterocyclic groups include, but are not limited to,pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl,and imidazolyl. Also included are fused ring and spiro compoundscontaining, for example, the above heterocycles.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking non-toxic acid or base salts thereof, and further refers topharmaceutically acceptable solvates of such compounds and such salts.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,malefic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. The pharmaceuticallyacceptable salts of the present invention can be synthesized from aparent compound that contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting freeacid forms of these compounds with a stoichiometric amount of theappropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate, or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, non-aqueous media like ether,ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred,where practicable. Lists of additional suitable salts may be found,e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack PublishingCompany, Easton, Pa., p. 1418 (1985).

“Prodrugs” are intended to include any compounds that become compoundsof Formula I when administered to a mammalian subject, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate and like derivativesof functional groups (such as alcohol or amine groups) in the compoundsof Formula I.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture, and subsequent formulation into an effectivetherapeutic agent. The term “therapeutically effective amount” of acompound of this invention means an amount effective, when administeredto a human or non-human patient, to provide a therapeutic benefit suchas an amelioration of symptoms, e.g., an amount effective to antagonizethe effects of pathogenic levels of CRF or to treat the symptoms ofstress disorders, affective disorder, anxiety or depression.

Pharmaceutical Preparations

The compounds of general Formula I may be administered orally,topically, transdermally, parenterally, by inhalation or spray orrectally or vaginally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneous,intravenous, intramuscular, intrathecal and like types of injection orinfusion techniques. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This, suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents that have been mentioned above. Thesterile injectable preparation may also be sterile injectable solutionor suspension in a non-toxic parentally acceptable dilutent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at body temperature and will therefore melt in the body torelease the drug. Such materials include cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, one or more adjuvants such as preservatives, bufferingagents, or local anesthetics can also be present in the vehicle.

Dosage levels of the order of from about 0.05 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions, preferred dosages range from about 0.1 toabout 30 mg per kg and more preferably from about 0.5 to about 5 mg perkg per subject per day. The amount of active ingredient that may becombined with the carrier materials to produce a single dosage form willvary depending upon the host treated and the particular mode ofadministration. Dosage unit forms will generally contain between fromabout 0.1 mg to about 750 mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most CNS andgastrointestinal disorders, a dosage regimen of four times daily,preferably three times daily, more preferably two times daily and mostpreferably once daily is contemplated. For the treatment of stress anddepression a dosage regimen of 1 or 2 times daily is particularlypreferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination (i.e. otherdrugs being used to treat the patient) and the severity of theparticular disease undergoing therapy.

Preferred compounds of the invention will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, such that the preferred oral dosage forms discussedabove can provide therapeutically effective levels of the compound invivo. Penetration of the blood brain barrier is necessary for mostcompounds used to treat CNS disorders, while low brain levels ofcompounds used to treat periphereal disorders are generally preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity, with non-toxic compounds being preferred. Penetrationof the blood brain barrier of a compound in humans may be predicted fromthe brain levels of the compound in laboratory animals given thecompound, e.g., intravenously.

Percentage of serum protein binding may be predicted from albuminbinding assays. Examples of such assays are described in a review byOravcová, et al. (Journal of Chromatography B (1996) volume 677, pages1-27). Preferred compounds exhibit reversible serum protein binding.Preferably this binding is less than 99%, more preferably less than 95%,even more preferably less than 90%, and most preferably less than 80%.

Frequency of administration is generally inversely proportional to thein vivo half-life of a compound. In vivo half-lives of compounds may bepredicted from in vitro assays of microsomal half-life as described byKuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26,pages 1120-1127). Preferred half lives are those allowing for apreferred frequency of administration.

As discussed above, preferred compounds of the invention exhibit goodactivity in standard in vitro CRF receptor binding assays, preferablythe assay as specified in Example 31, which follows. References hereinto “standard in vitro receptor binding assay” are intended to refer tothat protocol as defined in Example 31, which follows. Generallypreferred compounds of the invention have an IC₅₀ (half-maximalinhibitory concentration) of about 1 micromolar or less, still morepreferably and IC₅₀ of about 100 nanomolar or less even more preferablyan IC₅₀ of about 10 nanomolar or less or even 1 nanomolar or less insuch a defined standard in vitro CRF receptor binding assay asexemplified by Example 31 which follows.

EXAMPLES Preparation of Arylpyrimidinones

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include but are not limitedto those methods described below. Each of the references cited below arehereby incorporated herein by reference. Preferred methods for thepreparation of compounds of the present invention include, but are notlimited to, those described in Schemes I, II and III. Those who areskilled in the art will recognize that the starting materials may bevaried and additional steps employed to produce compounds encompassed bythe present invention. All references cited herein are herebyincorporated in their entirety herein by reference. The followingabbreviations are used herein: AcOH acetic acid DMFN,N-dimethylformamide DMSO Dimethylsulfoxide Et₂O diethyl ether EtOAcethyl acetate EtOH Ethanol LDA lithium diisopropylamide NaH sodiumhydride NaHMDS sodium HCl hydrochloric acid hexamethyldisilazane THFtetrahydrofuran EX# example number

According to the general method A, wherein R₁ and R₃ are as defined forformula I and Ha1 represents a halogen atom, suitably chloride orbromide. Compounds of formula IV can be prepared according to a knownliterature procedure (T. L. Cupps et al., Journal of Organic Chemistry1983, 48, 1060). The halopyrimidine IV can be converted toarylpyrimidine V by a transition metal-catalyzed coupling reaction witha metalloaryl reagent (Ar-[M]). More commonly employed reagent/catalystpairs include aryl boronic acid/palladium(0) (Suzuki reaction; N.Miyaura and A. Suzuki, Chemical Reviews 1995, 95, 2457), aryltrialkylstannane/palladium(0) (Stille reaction; T. N. Mitchell,Synthesis 1992, 803), arylzinc/palladium(0) and arylGrignard/nickel(II). Palladium(0) represents a catalytic system made ofa various combination of metal/ligand pair which includes, but notlimited to, tetrakis(triphenylphosphine)-palladium(0), palladium(II)acetate/tri(o-tolyl)phosphine, tris-(dibenzylideneacetone)dipalladium(0)/tri-tert-butyl-phosphine anddichloro[1,1′-bis(diphenylphosphine)-ferrocene]palladium(0). Nickel(II)represents a nickel-containing catalyst such as[1,2-bis(di-phenyl-phosphino)ethane]dichloronickel(II) and“[1,3-bis(diphenyl-phosphino)propane]dichloronickel(II). Reduction ofthe nitro group in V may be accomplished by a variety of methods knownin the art, including hydrogenation with hydrogen and transition metalcatalysts or the use of sodium hydrosulfite in aqueous solutions to giveVI. The amino pyrimidine VI may be transformed into VII by reductiveamination using aldehydes and reducing agents such as sodiumtriacetoxyborohydride in inert solvents. Depending on the substitutionon the aromatic group (Ar), the order of the steps in Scheme I may bealtered. For instance, for disubstituted aromatic analogs, compound IVmay first be coupled with a boronic acid, the nitro group reduced andthe resulting amine alkylated to give compounds of generic structureVII. Conversion of the methoxypyrimidine VII to the pyrimidinone VIIImay be carried out by a number of methods known in the art, includingfor example the use of hydrochloric acid, boron trichloride, borontribromide, acetic acid, trimethylsilyl bromide, trimethylsilylchloride, or aluminum tribromide, in a solvent such as dichloromethaneor DMF.

N-alkylation of pyrimidone VIII to the final target II may beaccomplished using a base such as but not limited to alkali metalhydride or alkali metal alkoxide in inert solvents such as but notlimited to THF, DMF, or methyl sulfoxide. Alkylation may be conductedusing alkyl halide, suitably bromide, iodide, tosylate or mesylate attemperatures ranging from −78° C. to 100° C.

The alkylation of the methyl group (or other alkyl group) on position 6of the pyrimidine (e.g. compound VI) may be accomplished using a strongbase such as but not limited to alkali metal hydride, alkali metalamide, or alkali metal alkoxide in inert solvents such as but notlimited to THF, DMF, or methyl sulfoxide. Alkylation may be conductedusing alkyl halide, suitably bromide, iodide, tosylate or mesylate attemperatures ranging from −78° C. to 100° C. Using the same methodsdescribed in Method A, compounds of the formula II can also be preparedas outlined in Scheme II

An alternative method for introducing the substituents R_(A) and R_(B)to give compounds of the formula II is outlined in Scheme III and may beaccomplished by a variety of methods known in the art. These includereaction of the amine IX with acid chlorides or anhydrides in thepresence of bases such as but not limited to triethylamine or pyridinein inert solvents such as dichloromethane or toluene. The N—H group isthen deprotonated by a strong base such as but not limited to alkalimetal hydride, alkali metal amide, or alkali metal alkoxide in inertsolvents such as but not limited to THF, DMF, or methyl sulfoxide.Alkylation may be conducted using alkyl halide, suitably bromide oriodide, at temperatures ranging from 0° C. to 100° C. Reduction of theamide XI with reducing agents such as but not limited to lithiumaluminum hydride, borane or diiso-butylaluminum hydride in inertsolvents such as but not limited to THF, ether, or toluene furnishescompounds of the formula XII. Using the same methods described in MethodA, compounds of the formula II can also be prepared as outlined inScheme III.

The preparation of the compounds of the present invention is illustratedfurther by the following examples, which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them.

Commercial reagents are used without further purification. Room orambient temperature refers to 20 to 25° C. Concentration in vacuoimplies the use of a rotary evaporator. TLC refers to thin layerchromatography. Proton nuclear magnetic resonance (¹H NMR) spectral dataare obtained at 300 or 400 MHz. Mass spectral data are obtained eitherby CI or APCI methods.

Example 15-Dipropylamino-2-(2-methoxy-4,6-dimethyl-phenyl)-3,6-dimethyl-3H-pyrimidin-4-one[Formula I: Ar=2-methoxy-4,6-dimethyl-phenyl; R₁═CH₃; R₂═N(CH₂CH₂CH₃)₂;R₃═CH₃]

A:4-Methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-5-nitro-pyrimidine.A solution of 2-chloro-4-methoxy-6-methyl-5-nitro-pyrimidine (2.03 g, 10mmol) and tetrakis(tri-phenylphosphine)palladium(0) (225 mg) inethyleneglycol dimethyl ether (50 mL) is stirred at room temperature for15 min, then 2-methoxy-4,6-dimethyl-benzeneboronic acid (3.60 g, 20mmol) and an aqueous solution of sodium carbonate (1.0 M, 10 mL) isadded sequentially. The mixture is stirred at 75° C. (oil bathtemperature) for 1.5 h, then diluted with 0.1 N sodium hydroxide andextracted twice with 1:1 hexane-ethyl ether. Combined extracts are dried(magnesium sulfate), filtered, concentrated, and submitted to flashchromatography on silica gel (1:1 hexane-ether) to give4-methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-5-nitro-pyrimidine.¹H NMR (CDCl₃, 400 MHz) δ 2.08 (s, 3H), 2.36 (s, 3H), 2.60 (s, 3H), 3.73(s, 3H), 4.08 (s, 3H), 6.62 (s, 1H), 6.68 (s, 1H); MS (CI) 304.

B:4-Methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-pyrimidin-5-ylamine.A solution of4-methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-5-nitro-pyrimidine(6.2 g, 20.4 mmol) in methanol (150 mL) is hydrogenated in the presenceof palladium catalyst (5%/C, 1 g) at 1 atm of hydrogen (balloon). After1 h the reaction mixture is purged with nitrogen, the catalyst isremoved by filtration through celite, and the solvent evaporated toproduce4-methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-pyrimidin-5-ylamineas a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 2.02 (s, 3H), 2.30 (s, 3H),2.40 (s, 3H), 3.50 (br, 2H), 3.72 (s, 3H), 3.98 (s, 3H), 6.60 (s, 1H),6.68 (s, 1H).

C:[4-Methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-pyrimidin-5-yl]-dipropylamine.To a solution of4-methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-pyrimidin-5-ylamine(2.5 g, 9.1 mmol) in 1,2-dichloroethane (120 mL) is addedpropionaldehyde (2.0 mL) and glacial acetic acid (2.2 mL). After 10minutes sodium triacetoxyborohydride (9.0 g) is added in one portion.After 3 h the volatiles are removed by rotary evaporation. The residueis partitioned between ethyl acetate and saturated aqueous sodiumbicarbonate, the layers are separated and the aqueous layer furtherextracted with ethyl acetate. The combined organics are washed withwater, brine, dried (magnesium sulfate), filtered and concentrated togive[4-methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-pyrimidin-5-yl]-dipropylamine.¹H NMR (CDCl₃, 400 MHz) 8 0.89 (t, 6H), 1.40 (m, 4H), 2.05 (s, 3H), 2.33(s, 3H), 2.53 (s, 3H), 2.95 (t, 4H), 3.73 (s, 3H), 3.93 (s, 3H), 6.62(s, 1H), 6.67 (s, 1H).

D.5-Dipropylamino-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-3H-pyrimidin-4-one.A stirred solution of[4-methoxy-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-pyrimidin-5-yl]-dipropyl-amine(3.45 g; 9.7 mmol) in concentrated aqueous hydrochloric acid (23 mL) isstirred at 100° C. (oil bath temperature) for 2 h. After cooling down toroom temperature, the reaction mixture is poured onto ice-water, andmade alkaline with a cold solution of concentrated aqueous ammonia. Aprecipitate is formed, and the supernatant liquid separated byfiltration. The precipitate is dissolved in ethyl acetate, and theresulting solution washed with water until neutral pH of the aqueousphase. The organic solution is dried (magnesium sulfate), and thesolvent evaporated under reduced pressure to yield5-dipropylamino-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-3H-pyrimidin-4-oneas an off-white solid: ¹H NMR (CDCl₃, 400 MHz) δ 0.89 (t, 6H), 1.43 (m,4H), 2.27 (s, 3H), 2.34 (s, 3H), 2.43 (s, 3H), 3.01 (t, 4H), 3.78 (s,3H), 6.61 (s, 1H), 6.71 (s, 1H), 9.26 (br, 1H); MS (CI) 344.

E: S-Dipropylamino-2-(2-methoxy-4,6-dimethyl-phenyl)-3,6-dimethyl-3H-pyrimidin-4-one. A solution of5-dipropylamino-2-(2-methoxy-4,6-dimethyl-phenyl)-6-methyl-3H-pyrimidin-4-one(130 mg, 0.33 mmol) in anhydrous DMSO (1.0 mL) is added to a clearsolution of NaH (40 mg, 60% in mineral oil, 1.0 mmol) in anhydrous DMSO(5 mL) under nitrogen atmosphere (balloon) at room temperature. After 90min, methyl iodide is added (100 μl). The mixture is stirred at roomtemperature for 2 h, and the reaction quenched by addition of water. Thecrude is diluted with ethyl ether, and washed with brine. The organicfraction is dried (magnesium sulfate), and the residue submitted toflash chromatography, eluting with ethyl acetate: hexanes (1:3), toproduce the title compound: ¹H NMR (CDCl₃, 400 MHz) δ 0.90 (t, 6H), 1.42(m, 4H), 2.08 (s, 3H), 2.35 (s, 3H), 2.41 (s, 3H), 3.01 (t, 4H), 3.21(s, 3H), 3.75 (s, 3H), 6.61 (s, 1H), 6.71 (s, 1H); MS (CI) 358.

EX#s 2-26 in the Table I may be prepared following the methods describedin Example 1. TABLE I

Ex# Ar R₁ R₃ ¹H-NMR MS Name  2 6-methoxy-2,4- Me Et 0.88 (t, 6H), 1.05(t, 3H), 372 5-Dipropylamino-2-(6- dimethylphenyl 1.40 (m, 4H), 2.05 (s,3H), methoxy-2,4-dimethyl- 2.32 (s, 3H), 2.37 (s, 3H),phenyl)-3-ethyl-6-methyl- 2.99 (m, 4H), 3.64 (m, 1H), 3H-pyrimidin-4-one3.73 (s, 3H), 3.81 (m, 1H), 6.58 (s, 1H), 6.67 (s, 1H)  3 6-methoxy-2,4-Me n-Pr 0.72 (t, 3H), 0.87 (t, 6H), 386 5-Dipropylamino-2-(6-dimethylphenyl 1.39 (m, 6H), 2.05 (s, 3H), methoxy-2,4-dimethyl- 2.32(s, 3H), 2.37 (s, 3H), phenyl)-3-propyl-6- 2.98 (m, 4H), 3.51 (m, 1H),methyl-3H-pyrimidin-4- 3.70 (m, 1H), 3.72 (s, 3H), one 6.57 (s, 1H),6.67 (s, 1H)  4 6-methoxy-2,4- Me i-Pr 0.90 (t, 6H), 1.42 (m, 4H), 3865-Dipropylamino-2-(6- dimethylphenyl 1.44 (d, 3H), 1.52 (d, 3H),methoxy-2,4-dimethyl- 2.10 (s, 3H), 2.35 (s, 3H), phenyl)-3-isopropyl-6-2.36 (s, 3H), 2.99 (m, 4H), methyl-3H-pyrimidin-4- 3.51 (m, 1H), 3.70(m, 1H), one 3.76 (s, 3H), 3.97 (m, 1H), 6.59 (s, 1H), 6.70 (s, 1H)  56-methoxy-2,4- Me Bn 0.92 (t, 6H), 1.45 (m, 4H), 4355-Dipropylamino-2-(6- dimethylphenyl 2.34 (s, 3H), 2.41 (s, 3H),methoxy-2,4-dimethyl- 3.07 (m, 4H), 3.59 (s, 3H),phenyl)-3-butyl-6-methyl- 4.57 (d, 1H), 5.36 (d, 1H), 3H-pyrimidin-4-one6.55 (s, 2H), 6.82 (d, 2H), 7.15 (m, 3H)  6 6-methoxy-2,4- Me —CH₂CH₂F0.89 (t, 6H), 1.41 (m, 4H), 390 5-Dipropylamino-2-(6- dimethylphenyl2.11 (s, 3H), 2.33 (s, 3H), methoxy-2,4-dimethyl- 2.39 (s, 3H), 2.99 (m,4H), phenyl)-3-(2-fluoroethyl)- 3.73 (s, 3H), 3.89 (m, 1H),6-methyl-3H-pyrimidin-4- 4.17 (m, 1H), 4.41 (m, 1H), one 4.63 (m, 1H),6.58 (s, 1H), 6.70 (s, 1H)  7 6-methoxy-2,4- Me —CH₂CF₃ 0.89 (t, 6H),1.42 (m, 4H), 427 5-Dipropylamino-2-(6- dimethylphenyl 2.15 (s, 3H),2.35 (s, 3H), methoxy-2,4-dimethyl- 2.41 (s, 3H), 3.01 (m, 4H),phenyl)-3-(2,2,2- 3.76 (s, 3H), 4.04 (m, 1H), trifluoroethyl)-6-methyl4.94 (m, 1H), 6.60 (s, 1H), 3H-pyrimidin-4-one 6.74 (s, 1H)  86-methoxy-2,4- Et H 0.87 (t, 6H), 1.12 (t, 3H), 3585-Dipropylamino-2-(6- dimethylphenyl 1.38 (m, 4H), 2.28 (s, 3H),methoxy-2,4-dimethyl- 2.33 (s, 3H), 2.83 (q, 2H), phenyl)-6-methyl-3H-2.90 (m, 4H), 3.75 (s, 3H), pyrimidin-4-one 6.59 (s, 1H), 6.70 (s, 1H),10.81 (br, 1H)  9 6-methoxy-2,4- Et Me 0.85 (t, 6H), 1.16 (t, 3H), 3725-Dipropylamino-2-(6- dimethylphenyl 1.40 (m, 4H), 2.04 (s, 3H),methoxy-2,4-dimethyl- 2.36 (s, 3H), 2.58 (dq, 1H),phenyl)-3-methyl-6-ethyl- 2.98 (m, 4H), 3.02 (dq, 1H),3H-pyrimidin-4-one 3.18 (s, 3H), 3.75 (s, 3H), 6.60 (s, 1H), 6.70 (s,1H) 10 6-methoxy-2,4- Et Et 0.90 (t, 6H), 1.07 (t, 3H), 3865-Dipropylamino-2-(6- dimethylphenyl 1.16 (t, 3H), 1.42 (m, 4H),methoxy-2,4-dimethyl- 2.08 (s, 3H), 2.35 (s, 3H),phenyl)-3-ethyl-6-ethyl- 2.57 (m, 1H), 3.01 (m, 5H), 3H-pyrimidin-4-one3.64 (m, 1H), 3.75 (s, 3H), 3.87 (m, 1H), 6.61 (s, 1H), 6.71 (s, 1H) 112,4,6- Et H 0.84 (t, 6H), 1.18 (t, 3H), 342 5-Dipropylamino-2-trimethylphenyl 1.38 (m, 4H), 2.18 (s, 6H), (2,4,6-trimethyl-phenyl)-2.28 (s, 3H), 2.92 (m, 6H), 6-ethyl-3H-pyrimidin-4- 7.85 (s, 2H) one 122,4,6- Me H 0.84 (t, 6H), 1.36 (m, 4H), 328 5-Dipropylamino-2-trimethylphenyl 2.14 (s, 6H), 2.28 (s, 3H), (2,4,6-trimethyl-phenyl)-2.42 (s, 3H), 2.95 (m, 4H), 6-methyl-3H-pyrimidin-4- 5.30 (s, 1H), 7.85(s, 2H) one 13 2,4,6- Me Et 0.88 (t, 6H), 1.05 (t, 3H), 3565-Dipropylamino-2- trimethylphenyl 1.40 (m, 4H), 2.06 (s, 6H),(2,4,6-trimethyl-phenyl)- 2.32 (s, 3H), 2.39 (s, 3H),3-ethyl-6-methyl-3H- 3.00 (m, 4H), 3.72 (q, 2H), pyrimidin-4-one 6.90(s, 2H) 14 2,4,6- trimethylphenyl Me

0.88 (t, 6H), 1.40 (m, 4H), 1.62 (br s, 4H), 2.06 (s, 6H), 2.14 (s, 3H),2.32 (br s, 2H), 2.37 (s, 3H), 2.57 (m, 4H), 2.98 (m, 4H), 3.81 (m, 2H),6.83 (s, 2H) 425 5-Dipropylamino-6- methyl-3-(2-pyrrolidin-1-yl-ethyl)-2-(2,4,6- trimethyl-phenyl)-3H- pyrimidin-4-one 15 2,4- Me Et0.90 (t, 6H), 1.12 (t, 3H), 382 5-Dipropylamino-2-(2,4- dichlorophenyl1.40 (m, 4H), 2.38 (s, 3H), dichloro-phenyl)-3-ethyl- 3.00 (m, 4H), 3.45(dq, 1H), 6-methyl-3H-pyrimidin-4- 4.15 (dq, 1H), 7.38 (m, 2H), one 7.55(s, 1H) 16 2,4- Me H 0.84 (t, 6H), 1.40 (m, 4H), 3465-Dipropylamino-2-(2,4- dimethoxyphenyl 2.42 (s, 3H), 2.98 (m, 4H),dimethoxy-phenyl)-6- 3.83 (s, 3H), 3.99 (s, 3H), methyl-3H-pyrimidin-4-6.47 (s, 1H), 6.63 (d, 1H), one 8.40 (d, 1H) 17 2,4- Me Me 0.95 (t, 6H),1.42 (m, 4H), 360 5-Dipropylamino-2-(2,4- dimethoxyphenyl 2.40 (s, 3H),3.00 (m, 4H), dimethoxy-phenyl)-3,6- 3.24 (s, 3H), 3.78 (s, 3H),dimethyl-3H-pyrimidin-4- 3.84 (s, 3H), 6.54 (s, 1H), one 6.58 (d, 1H),7.24 (d, 1H) 18 2,4- Me Et 0.92 (t, 6H), 1.05 (t, 3H), 3765-Dipropylamino-2-(2,4- dimethoxyphenyl 1.42 (m, 4H), 2.38 (s, 3H),dimethoxy-phenyl)-3- 3.00 (m, 4H), 3.46 (dq, 1H), ethyl-6-methyl-3H-3.78 (s, 3H), 3.86 (s, 3H), pyrimidin-4-one 4.15 (dq, 1H), 6.52 (s, 1H),6.58 (d, 1H), 7.28 (d, 1H) 19 2,4- Me n-Pr 0.86 (t, 6H), 0.94 (t, 6H),390 5-Dipropylamino-2-(2,4- dimethoxyphenyl 1.40-1.50 (m, 6H), 2.38 (s,dimethoxy-phenyl)-3- 3H), 2.98 (m, 4H), 3.36 (m, propyl-6-methyl-3H-1H), 3.78 (s, 3H), 3.84 (s, pyrimidin-4-one 3H), 4.06 (m, 1H), 6.45 (s,1H), 6.58 (d, 1H), 7.26 (d, 1H) 20 2,4- dimethoxyphenyl Me

−0.05 (m, 1H), 0.18 (m, 1H), 0.38 (m, 2H), 0.92 (t, 6H), 1.42 (m, 4H),2.40 (s, 3H), 3.00 (m, 4H), 3.21 (dd, 1H), 3.78 (s, 3H), 3.84 (s, 3H),4.22 (dd, 1H), 6.44 (s, 1H), 6.58 (d, 1H), 7.30 (d, 1H) 4005-Dipropylamino-2-(2,4- dimethoxy-phenyl)-3- cyclpropylmethyl-6-methyl-3H-pyrimidin-4- one 21 2,4- Me —CH₂CH₂OMe 0.92 (t, 6H), 1.42 (m,4H), 404 5-Dipropylamino-2-(2,4- dimethoxyphenyl 2.40 (s, 3H), 3.00 (m,4H), dimethoxy-phenyl)-3-(2- 3.18 (s, 3H), 3.4-3.6 (m,methoxy-ethyl)-6-methyl- 2H), 3.65 (dq, 1H), 3.80 (s, 3H-pyrimidin-4-one3H), 3.82 (s, 3H), 4.37 (dq, 1H), 6.44 (s, 1H), 6.60 (d, 1H), 7.24 (d,1H) 22 2-Methoxy,6- Me H 5-Dipropylamino-2-(2- trifluoromethoxymethoxy-6- phenyl trifluoromethoxy-phenyl) 6-methyl-3H-pyrimidin-4- one23 2-Methoxy,6- Me —CH₂CH₃ 5-Dipropylamino-2-(2- trifluoromethoxymethoxy-6- phenyl trifluoromethoxy-phenyl)- 3-ethyl-6-methyl-3H-pyrimidin-4-one 24 2,6- Me methyl 5-Dipropylamino-2-(2,6-Dimethoxyphenyl dimethoxyphenyl)-3,6- dimethyl-3H-pyrimidin-4- one 252,6- Me —CH₂CH₃ 5-Dipropylamino-2-(2,6- Dimethoxyphenyldimethoxyphenyl)-3- ethyl-6-methyl-3H- pyrimidin-4-one 26 2,6- Me H5-Dipropylamino-2-(2,6- Dimethoxyphenyl dimethoxyphenyl)-6-methyl-3H-pyrimidin-4- one

Example 275-(Cyclopropylmethyl-propyl-amino)-2-(2,4-dimethoxy-phenyl)-6-ethyl-3-(2-fluoro-ethyl)-3H-pyrimidin-4-one

A: [2-(2,4-Dimethoxy-phenyl)-4-methyl-6-methoxy-pyrimidin-5-yl]-amide. Asolution of2-(2,4-Dimethoxy-phenyl)-4-ethyl-6-methoxy-pyrimidin-5-ylamine (1.3 g,4.72 mmol) in ethyl acetate (30 mL) was treated with triethylamine (606mg, 6.0 mmol) and cyclopropylcarbonyl chloride (624 mg, 6 mmol), andstirred under nitrogen atmosphere at room temperature for 16 h. Thereaction mixture was diluted with sodium bicarbonate (saturatedsolution) and partitioned between ethyl acetate and brine. The organiclayer was separated, dried (magnesium sulfate) and the solventevaporated under reduced pressure to yield the title compound, (1.42 g,88%). ¹H NMR (CDCl₃, 400 MHz) δ 0.84 (m, 2H), 1.10 (m, 2H), 1.62 (m,1H), 2.42 (s, 3H), 3.86 (s, 6H), 4.02 (s, 3H), 6.58 (s, 1H), 6.60 (d,1H), 7.00 (br, 1H), 7.86 (d, 1H); MS (CI) 344.

B: Cyclopropanecarboxylic acid[2-(2,4-dimethoxy-phenyl)-4-methyl-6-methoxy-pyrimidin-5-yl]-propyl-amide.A solution of cyclopropanecarboxylic acid[2-(2,4-dimethoxy-phenyl)4-methyl-6-methoxy-pyrimidin-5-yl]-amide (1.3g, 3.8 mmol) and iodoethane (1.02 g, 6.0 mmol) in anhydrous DMF (30 mL)is treated with sodium hydride (240 mg, 6.0 mmol) and heated at 60° C.for 3 h. The reaction mixture is cooled down to room temperature, andpartitioned between ethyl acetate and sodium bicarbonate (saturatedsolution). The organic layer is washed with brine, dried, and thesolvent removed under reduced pressure, to produce the title compound.¹H NMR (CDCl₃, 400 MHz) δ 0.60 (m, 2H), 0.85 (t, 6H), 1.02 (m, 2H), 1.20(m, 11H), 1.56 (m, 2H), 2.44 (s, 3H), 3.46 (m, 2H), 3.84 (s, 3H), 3.86(s, 3H), 4.02 (s, 3H), 6.58 (s, 1H), 6.60 (d, 1H), 7.90 (d, 1H); MS (CI)386.

C: Cyclopropanecarboxylic acid[2-(2,4-dimethoxy-phenyl)-4-ethyl-6-methoxy-pyrimidin-5-yl]-propyl-amide.To a solution of LDA (8.0 mmol) in THF (35 mL) at −78° C. under nitrogenatmosphere is added cyclopropanecarboxylic acid[2-(2,4-dimethoxy-phenyl)-4-methyl-6-methoxy-pyrimidin-5-yl]-propyl-amide(2.6 g, 6.7 mmol). After 15 min methyl iodide (1.4 mL, 10 mmol) is addeddropwise. An hour later the reaction is quenched by addition of water,and extracted into ethyl ether. The organic layer is washed, dried(magnesium sulfate) and the solvents removed under reduced pressure.Chromatographic purification is carried out on silica gel, eluting withhexanes:ethyl ether (1:1), yielding of title compound. ¹H NMR (CDCl₃,400 MHz) δ 0.60 (m, 2H), 0.85 (t, 6H), 1.20 (m, 1H), 1.28 (t, 3H), 1.56(m, 2H), 2.78 (m, 2H), 3.46 (m, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 4.02(s, 3H), 6.58 (s, 1H), 6.60 (d, 1H), 7.98 (d, 1H).

D.Cyclopropyl-methyl-[2-(2,4-dimethoxy-phenyl)-4-ethyl-6-methoxy-pyrimidin-5-yl]-propyl-amine.To a solution of cyclopropanecarboxylic acid[2-(2,4-dimethoxy-phenyl)-4-ethyl-6-methoxy-pyrimidin-5-yl]-propyl-amide(397 mg, 1.0 mmol) in THF (8 mL) at 0° C. under nitrogen atmosphere isadded DIBAL (1.0 mmol, 1M solution in hexanes, 1.0 mL). After 3 h atroom temperature the reaction is quenched with ammonium chloride(saturated solution, 5 mL) and then neutralized with sodium hydroxide (4M). The crude is extracted into ethyl ether, washed with brine, dried(magnesium sulfate) and the solvents removed under reduced pressure. Thetitle compound is obtained as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ0.00 (d, 1H), 0.38 (d, 1H), 0.80 (m, 1H), 0.85 (t, 6H), 1.28 (t, 3H),1.4 (m, 1H), 2.80 (m, 1H), 2.92 (t, 2H), 3.02 (t, 2H), 3.84 (s, 3H),3.86 (s, 3H), 4.00 (s, 3H), 6.57 (s, 1H), 6.59 (d, 1H), 7.82 (d, 1H); MS(CI) 387.

E.5-(cyclopropylmethyl-propyl-amino)-2-(2,4-dimethoxy-phenyl)-6-ethyl-3H-pyrimidin-4-one.A stirred solution ofcyclopropyl-methyl-[2-(2,4-dimethoxy-phenyl)-4-ethyl-6-methoxy-pyrimidin-5-yl]-propyl-amine(200 mg; 0.52 mmol) in concentrated aqueous hydrochloric acid (2.0 mL)is stirred at 100° C. (oil bath temperature) for 2 h. After cooling downto room temperature, the reaction mixture is poured onto ice-water, andmade alkaline with a cold solution of concentrated aqueous ammonia. Aprecipitate is formed, and the supernatant liquid separated byfiltration. The precipitate is dissolved in ethyl acetate, and theresulting solution washed with water until neutral pH of the aqueousphase. The organic solution is dried (magnesium sulfate), and thesolvent evaporated under reduced pressure to yield5-(cyclopropylmethyl-propyl-amino)-2-(2,4-dimethoxy-phenyl)-6-ethyl-3H-pyrimidin-4-oneas an off-white solid. MS (CI) 372.

F:5-(Cyclopropylmethyl-propyl-amino)-2-(2,4-dimethoxy-phenyl)-6-ethyl-3-(2-fluoro-ethyl)-3H-pyrimidin-4-one.A solution of5-(cyclopropylmethyl-propyl-amino)-2-(2,4-dimethoxy-phenyl)-6-ethyl-3H-pyrimidin-4-one(173 mg, 0.46 mmol) is added to a clear solution of NaH (60 mg, 60% inmineral oil, 1.5 mmol) in anhydrous DMSO (4.0 mL) under nitrogenatmosphere (balloon) at room temperature. After 60 min,1-fluoro-2-iodoethane is added (258 mg, 1.5 mmol). The mixture isstirred at room temperature for 2 h, and the reaction quenched byaddition of water. The crude is diluted with ethyl ether, and washedwith brine. The organic fraction is dried (magnesium sulfate), and theresidue submitted to preparative thin layer chromatography, eluting withethyl ether: hexanes (1:1), to produce the title compound. ¹H NMR(CDCl₃, 400 MHz) δ 0.05 (d, 1H), 0.38 (d, 1H), 0.80 (m, 1H), 0.86 (t,3H), 0.97 (t, 1H), 1.20 (t,,3H), 1.32 (t, 1H), 1.42 (m, 2H), 2.66 (m,1H), 2.80 (q, 1H), 2.90 (m, 2H), 3.04 (m, 2H), 3.76 (s, 3H), 3.82 (s;3H), 3.83 (m, 1H), 4.35-4.45 (m, 2H), 4.64 (m, 1H), 6.47 (s, 1H), 6.60(d, 1H), 7.28 (d, 1H); MS (CI) 418.

EX#s 28-30 in the Table II may be prepared following the methodsdescribed in Example 27. TABLE II

Ex# Ar R₁ R₂ ¹H-NMR MS Name 28 2,4-dimethoxyphenyl Et CH₂CH₂F 0.03 (d,1H), 0.38 419 5- (d, 1H), 0.8 (m, (Cyclopropylmethyl- 1H), 0.89 (t, 3H),propyl-amino)-2- 1.22 (t, 3H), 1.41 (2,4-dimethoxy- (m, 2H), 2.11 (s,phenyl)-3-(2- 3H), 2.33 (s, 3H), fluoro-ethyl)-6- 2.39, 2.6-3.1 (m,ethyl-3H- 6H), 3.78 (s, 3H), pyrimidin-4-one 3.85 (s, 3H), 4.3- 4.7 (m,4H), 6.45 (s, 1H), 6.60 (d, 1H), 7.30 (d, 1H) 29

Et H 0.03 (d, 1H), 0.38 (d, 1H), 0.8 (m, 1H), 0.89 (t, 3H), 1.22 (t,3H), 1.42 (m, 1H), 1.62 (m, 1H), 2.25 (s, 3H), 2.28 (s, 3H), 2.45 (br,3H), 2.62 (m, 3H), 2.90 (m, 2H), 3.06 (m, 1H), 3.12 (m, 1H), 3.5-3.6 (m,4H), 4.26 (m, 2H), 6.62 (s, 1H), 6.78 (s, 1R) 470 5- (Cyclopropylmethyl-propyl-amino)-2- [2,4-dimethyl-6-(2- morpholin-4-yl- ethoxy)-phenyl]-6-ethyl-3H- pyrimidin-4-one 30

Et Et 0.03 (d, 1H), 0.38 (d, 1H), 0.8-1.5 (m, 15H), 1.62 (m, 1H), 2.06(s, 3H), 2.28 (s, 3H), 2.40 (m, 2H), 2.45 (br, 3H), 2.60 (m, 3H),2.95-3.08 (m, 4H), 3.12 (m, 1H), 3.5-3.6 (m, 4H), 3.85 (dq, 1H), 4.08(m, 2H), 4.12 (dq, 1H), 6.58 (s, 1H), 6.78 (s, 1H) 498 5-(Cyclopropylmethyl- propyl-amino)-2- [2,4-dimethyl-6-(2- morpholin-4-yl-ethoxy)-phenyl]- 3,6-diethyl-3H- pyrimidin-4-one

Example 31

Assay for CRF Receptor Binding Activity

As discussed above, the following assay is defined herein as a standardin vitro CRF receptor binding assay.

The pharmaceutical utility of compounds of this invention is indicatedby the following assay for CRF1 receptor activity. The CRF receptorbinding is performed using a modified version of the assay described byGrigoriadis and De Souza (Methods in Neurosciences, Vol. 5, 1991).IMR-32 human neuroblastoma cells, a cell-line that naturally expressesthe CRF1 receptor, are grown in IMR-32 Medium, which consists of EMEMw/Earle's BSS (JRH Biosciences, Cat# 51411) plus, as supplements, 2 mML-Glutamine, 10% Fetal Bovine Serum, 25 mM HEPES (pH 7.2), 1 mM SodiumPyruvate and Non-Essential Amino Acids (JRH Biosciences, Cat# 58572).The cells are grown to confluence and split three times (all splits andharvest are carried out using NO-ZYME—JRH Biosciences, Cat# 59226). Thecells are first split 1:2, incubated for 3 days and split 1:3, andfinally incubated for 4 days and split 1:5. The cells are then incubatedfor an additional 4 days before being differentiated by treatment with5-bromo-2′deoxyuridine (BrdU, Sigma, Cat# B9285). The medium is replacedevery 3-4 days with IMR-32 medium w/2.5 uM BrdU and the cells areharvested after 10 days of BrdU treatment and washed with calcium andmagnesium-free PBS.

To prepare receptor containing membranes cells are homogenized in washbuffer (50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4) and centrifugedat 48,000×g for 10 minutes at 4° C. The pellet is re-suspended in washbuffer and the homogenization and centrifugation steps are performed twoadditional times.

Membrane pellets (containing CRF receptors) are re-suspended in 50 mMTris buffer pH 7.7 containing 10 mM MgCl₂ and 2 mM EDTA and centrifugedfor 10 minutes at 48,000 g. Membranes are washed again and brought to afinal concentration of 1500 ug/ml in binding buffer (Tris buffer abovewith 0.1% BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.). For thebinding assay, 100 ul of the membrane preparation are added to 96 wellmicrotube plates containing 100 ul of ¹²⁵I-CRF (SA 2200 Ci/mmol, finalconcentration of 100 pM) and 50 ul of test compound. Binding is carriedout at room temperature for 2 hours. Plates are then harvested on aBRANDEL 96 well cell harvester and filters are counted for gammaemissions on a Wallac 1205 BETAPLATE liquid scintillation counter.Non-specific binding is defined by 1 mM cold CRF. IC₅₀ values arecalculated with the non-linear curve fitting program RS/1 (BBN SoftwareProducts Corp., Cambridge, Mass.). The binding affinity for thecompounds of Formula I expressed as IC₅₀ value, generally ranges fromabout 0.5 nanomolar to about 10 micromolar. Preferred compounds ofFormula I exhibit IC₅₀ values of less than or equal to 1.5 micromolar,more preferred compounds of Formula I exhibit IC₅₀ values of less than500 nanomolar, still more preferred compounds of Formula I exhibit IC₅₀values of less than 100 nanomolar, and most preferred compound ofFormula I exhibit IC₅₀ values of less than 10 nanomolar. The compoundsshown in Examples 1-33 have been tested in this assay and found toexhibit IC₅₀ values of less than or equal to 4 micromolar.

Example 32

Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SR₁International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in trifiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 33

Receptor Autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExamples.

Example 34

Additional Aspects of Preferred Compounds of the Invention

The most preferred compounds of the invention are suitable forpharmaceutical use in treating human patients. Accordingly, suchpreferred compounds are non-toxic. They do not exhibit single ormultiple dose acute or long-term toxicity, mutagenicity (e.g., asdetermined in a bacterial reverse mutation assay such as an Ames test),teratogenicity, tumorogenicity, or the like, and rarely trigger adverseeffects (side effects) when administered at therapeutically effectivedosages.

Preferably, administration of such preferred compounds of the inventionat certain doses (i.e., doses yielding therapeutically effective in vivoconcentrations or preferably doses of 10, 50, 100, 150, or 200 mg/kgadministered parenterally or prefrerably orally) does not result inprolongation of heart QT intervals (i.e., as determined byelectrocardiography, e.g., in guinea pigs, minipigs or dogs). Whenadministered daily for 5 or preferably ten days, such doses of suchpreferred compounds also do not cause liver enlargement resulting in anincrease of liver to body weight ratio of more than 100%, preferably notmore than 75% and more preferably not more than 50% over matchedcontrols in laboratory rodents (e.g., mice or rats). In another aspectsuch doses of such preferred compounds also preferably do not causeliver enlargement resulting in an increase of liver to body weight ratioof more than 50%, preferably preferably not more than 25%, and morepreferably not more than 10% over matched untreated controls in dogs orother non-rodent mammals.

In yet another aspect such doses of such preferred compounds alsopreferably do not promote the release of liver enzymes (e.g., ALT, LDH,or AST) from hepatocytes in vivo. Preferably such doses do not elevateserum levels of such enzymes by more than 100%, preferably not by morethan 75% and more preferably not by more than 50% over matched untreatedcontrols in laboratory rodents. Similarly, concentrations (in culturemedia or other such solutions that are contacted and incubated withcells in vitro) equivalent to two, fold, preferably five-fold, and mostpreferably ten-fold the minimum in vivo therapeutic concentration do notcause release of any of such liver enzymes from hepatocytes into culturemedium in vitro above baseline levels seen in media from untreatedcells.

Because side effects are often due to undesirable receptor activation orantagonism, preferred compounds of the invention exert theirreceptor-modulatory effects with high selectivity. This means that theydo not bind to certain other receptors (other than CRF receptors) withhigh affinity, but rather only bind to, activate, or inhibit theactivity of such other receptors with affinity constants of greater than100 nanomolar, preferably greater than 1 micromolar, more preferablygreater than 10 micromolar and most preferably greater than 100micromolar. Such receptors preferably are selected from the groupincluding ion channel receptors, including sodium ion channel receptors,neurotransmitter receptors such as alpha- and beta-adrenergic receptors,muscarinic receptors (particularly ml, m2, and m3 receptors), dopaminereceptors, and metabotropic glutamate receptors; and also includehistamine receptors and cytokine receptors, e.g., interleukin receptors,particularly IL-8 receptors. The group of other receptors to whichpreferred compounds do not bind with high affinity also includesGABA_(A) receptors, bioactive peptide receptors (including NPY and VIPreceptors), neurokinin receptors, bradykinin receptors (e.g., BK1receptors and BK2 receptors), and hormone receptors (includingthyrotropin releasing hormone receptors and melanocyte-concentratinghormone receptors).

Example 34a

Absence of Sodium Ion Channel Activity

Preferred compounds of the invention do not exhibit activity as sodiumion channel blockers. Sodium channel activity may be measured a standardin vitro sodium channel binding assays such as the assay given by Brownet al. (J. Neurosci. 1986, 265, 17995-18004). Preferred compounds of theinvention exhibit less than 15 percent inhibition, and more preferablyless than 10 percent inhibition, of sodium channel specific ligandbinding when present at a concentration of 4 uM. The sodium ion channelspecific ligand used may be labeled batrachotoxinin, tetrodotoxin, orsaxitoxin. Such assays, including the assay of Brown referred to above,are performed as a commercial service by CEREP, Inc., Redmond, Wash.

Alternatively, sodium ion channel activity may be measured in vivo in anassay of anti-epileptic activity. Anti-epileptic activity of compoundsmay be measured by the ability of the compounds to inhibit hind limbextension in the supra maximal electro shock model. Male Han Wistar rats(150-200 mg) are dosed i.p. with a suspension of 1 to 20 mg of testcompound in 0.25% methylcellulose 2 hr. prior to test. A visualobservation is carried out just prior to testing for the presence ofataxia. Using auricular electrodes a current of 200 mA, duration 200millisec, is applied and the presence or absence of hind limb extensionis noted. Preferred compounds of the invention do not exhibitsignificant anti-epileptic activity at the p<0.1 level of significanceor more preferably at the p<0.05 level of significance as measured usinga standard parametric assay of statistical significance such as astudent's T test.

Example 34b

Microsomal In Vitro Half-Life

Compound half-life values (t_(1/2) values) may be determined via thefollowing standard liver microsomal half-life assay. Pooled Human livermicrosomes are obtained from XenoTech LLC, 3800 Cambridge St. Kansas'sCity, Kans., 66103 (catalog # H0610). Such liver microsomes may also beobtained from In Vitro Technologies, 1450 South Rolling Road, Baltamore,Md. 21227, or from Tissue Transformation Technologies, Edison CorporateCenter, 175 May Street, Suite 600, Edison, N.J. 08837. Reactions arepreformed as follows:

Reagents:

Phosphate buffer: 19 mL 0.1 M NaH₂PO₄, 81 mL 0.1 Na₂HPO₄, adjusted to pH7.4 with H₃PO₄.

CoFactor Mixture: 16.2 mg NADP, 45.4 mg Glucose-6-phosphate in 4 mL 100mM MgCl₂.

Glucose-6-phosphate dehydrogenase: 214.3 ul glucose-6-phosphatedehydrogenase suspension (Boehringer-Manheim catalog no. 0737224,distributed by Roche Molecular Biochemicals, 9115 Hague Road, P.O. Box50414, Indianapolis, Ind. 46250) is diluted into 1285.7 ul distilledwater.

Starting Reaction Mixture: 3 mL CoFactor Mixture, 1.2 mLGlucose-6-phosphate dehydrogenase.

Reaction:

6 test reactions are prepared, each containing 25 ul microsomes, 5 ul ofa 100 uM solution of test compound, and 399 ul 0.1 M phosphate buffer. Aseventh reaction is prepared as a positive-control containing 25 ulmicrosomes, 399 ul 0.1 M phosphate buffer, and 5 ul of a 100 uM solutionof a compound with known metabolic properties (e.g. DIAZEPAM orCLOZEPINE). Reactions are preincubated at 39° C. for 10 minutes. 71 ulStarting Reaction Mixture is added to 5 of the 6 test reactions and tothe positive control, 71 ul 100 mM MgCl₂ is added to the sixth testreaction, which is used as a negative control. At each time point (0, 1,3, 5, and 10 minutes) 75 ul of each reaction mix is pipetted into a wellof a 96-well deep-well plate containing 75 ul ice-cold acetonitrile.Samples are vortexed and centrifuged 10 minutes at 3500 rpm (Sorval T6000D centrifuge, H1000B rotor). 75 ul of supernatant from each reactionis transferred to a well of a 96-well plate containing 150 ul of a 0.5uM solution of a compound with a known LCMS profile (internal standard)per well. LCMS analysis of each sample is carried out and the amount ofunmetabolized test compound is measured as AUC, compound concentrationvs time is plotted, and the t_(1/2) value of the test compound isextrapolated.

Preferred compounds of the invention exhibit in vitro t_(1/2) values ofgreater than 10 minutes and less than 4 hours. Most preferred compoundsof the invention exhibit in vitro t_(1/2) values of between 30 minutesand 1 hour in human liver microsomes.

Example 34c

MDCK Toxicity Assay

Compounds causing acute cytotoxicity will decrease ATP production byMadin Darby canine kidney (MDCK) cells in the following assay.

MDCK cells, ATCC no. CCL-34 (American Type Culture Collection, Manassas,Va.) are maintained in sterile conditions following the instructions inthe ATCC production information sheet. The PACKAR_(D), (Meriden, Conn.)ATP-LITE-M Luminescent ATP detection kit, product no. 6016941, allowsmeasurement ATP production in MDCK cells.

Prior to assay 1 ul of test compound or control sample is pipetted intoPACKARD (Meriden, Conn.) clear bottom 96-well plates. Test compounds andcontrol samples are diluted in DMSO to give final concentration in theassay of 10 micromolar, 100 micromolar, or 200 micromolar. Controlsamples are drug or other compounds having known toxicity properties.

Confluent MDCK cells are trypsinized, harvested, and diluted to aconcentration of 0.1×10⁶ cells/ml with warm (37° C.) VITACELL MinimumEssential Medium Eagle (ATCC catalog # 30-2003). 100 ul of cells inmedium is pipetted into each of all but five wells of each 96-wellplate. Warm medium without cells (100 ul) is pipetted in the remainingfive wells of each plate to provide standard curve control wells. Thesewells, to which no cells are added, are used to determine the standardcurve. The plates are then incubated at 37° C. under 95% O₂, 5% CO₂ for2 hours with constant shaking. After incubation, 50 ul of mammalian celllysis solution is added per well, the wells are covered with PACKARDTOPSEAL stickers, and plates are shaken at approximately 700 rpm on asuitable shaker for 2 minutes.

During the incubation, PACKARD ATP LITE-M reagents are allowed toequilibrate to room temperature. Once equilibrated the lyophilizedsubstrate solution is reconstituted in 5.5 mls of substrate buffersolution (from kit). Lyophilized ATP standard solution is reconstitutedin deionized water to give a 10 mM stock. For the five control wells, 10ul of serially diluted PACKARD standard is added to each of the fivestandard curve control wells to yield a final concentration in eachsubsequent well of 200 nM, 100 nM, 50 nM, 25 nM, and 12.5 nM.

PACKARD substrate solution (50 ul) is added to all wells. Wells arecovered with PACKARD TOPSEAL stickers, and plates are shaken atapproximately 700 rpm on a suitable shaker for 2 minutes. A whitePACKARD sticker is attached to the bottom of each plate and samples aredark adapted by wrapping plates in foil and placing in the dark for 10minutes. Luminescence is then measured at 22° C. using a luminescencecounter, e.g. PACKARD TOPCOUNT Microplate Scintillation and LuminescenseCounter or TECAN SPECTRAFLUOR PLUS.

Luminescence values at each drug concentration are compared to thevalues computed from the standard curve for that concentration.Preferred test compounds exhibit luminescence values 80% or more of thestandard, or preferably 90% or more of the standard, when a 10micromolar (uM) concentration of the test compound is used. When a 100uM concentration of the test compound is used, preferred test compoundsexhibit luminescence values 50% or more of the standard, or morepreferably 80% or more of the standard.

1. (canceled)
 2. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar is chosenfrom phenyl optionally substituted with up to 5 groups R_(A), naphthyloptionally substituted with up to 5 groups R_(A), and heteroaryloptionally substituted with up to 5 groups R_(A), said heteroaryl havingfrom 1 to 3 rings, 5 to 7 ring members in each ring and, in at least oneof said rings, from 1 to about 3 heteroatoms selected from the groupconsisting of N, O, and S; R is oxygen, methyl, or absent; R₁ is chosenfrom hydrogen, halogen, hydroxy, cyano, nitro, haloalkyl, haloalkoxy,alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, mono-and di-aminoalkyl, and —S(O)_(n)alkyl; R₂ is C₃₋₆alkoxyC₃₋₆cycloalkylalkoxy, NHR_(C), NR_(C), NR_(C)R_(D), or Y; R₃ ishydrogen; R_(A) is independently selected at each occurrence fromhalogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, alkylsubstituted with 0-2 R_(B), alkenyl substituted with 0-2 R_(B), alkynylsubstituted with 0-2 R_(B), cycloalkyl substituted with 0-2 R_(B),(cycloalkyl)alkyl substituted with 0-2 R_(B), alkoxy substituted with0-2 R_(B), —NH(alkyl) substituted with 0-2 R_(B), —N(alkyl)(alkyl) ofwhich each alkyl is independently substituted with 0-2 R_(B), —XR_(C),and Y; R_(B) is independently selected at each occurrence from the groupconsisting of halogen, hydroxy, cyano, amino, alkyl, —O(alkyl),—NH(alkyl), —N(alkyl)(alkyl), —S(O)_(n)(alkyl), haloalkyl, haloalkoxy,CO(alkyl), CONH(alkyl), CON(alkyl)(alkyl), —XR_(C), and Y; R_(C) andR_(D), which may be the same or different, are independently selected ateach occurrence from: hydrogen, and straight, branched, and cyclic alkylgroups, and (cycloalkyl)alkyl groups, said straight, branched, andcyclic alkyl groups, and (cycloalkyl)alkyl groups consist of 1 to 8carbon atoms, and contain zero or one or more double or triple bonds,each of which 1 to 8 carbon atoms may be further substituted with one ormore substituent(s) independently selected from oxo, hydroxy, halogen,cyano, amino, C₁-C₆alkoxy, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)(C₁-C₆alkyl),—NHC(═O)(C₁-C₆alkyl), —N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl),—NHS(O)_(n)(C₁-C₆alkyl), —S(O)_(n)(C₁-C₆alkyl), —S(O)_(n)NH(C₁-C₆alkyl),—S(O)_(n)N(C₁-C₆alkyl)(C₁-C₆alkyl), and Z; X is independently selectedat each occurrence from the group consisting of —CH₂—, —CHR_(D)—, —O—,—C(═O)—, —C(═O)O—, —S(O)_(n)—, —NH—, —NR_(D)—, —C(═O)NH—, —C(═O)NR_(D)—,—S(O)_(n)NH—, —S(O)_(n)NR_(D)—, —OC(═S)S—, —NHC(═O)—, —NR_(D)C(═O)—,—NHS(O)_(n)—, —OSiH₂—, —OSiH(C₁-C₄alkyl)-,—OSi(C₁-C₄alkyl)(C₁-C₄alkyl)-, and —NR_(D)S(O)_(n)—; Y and Z areindependently selected at each occurrence from: 3- to 7-memberedcarbocyclic or heterocyclic groups which are saturated, unsaturated, oraromatic, which may be further substituted with one or more substituentsindependently selected from halogen, oxo, hydroxy, amino, cyano, alkyl,—O(alkyl), —NH(alkyl), —N(alkyl)(alkyl), and —S(O)_(n)(alkyl), whereinsaid 3- to 7-membered heterocyclic groups contain one or moreheteroatom(s) independently selected from N, O, and S, with the point ofattachment being either carbon or nitrogen; and n is independentlyselected at each occurrence from 0, 1, and 2; provided that R₁ is nothydrogen, alkyl, or trifluoromethyl when R₂ is hydrogen, alkyl oralkenyl.
 3. A compound or salt according to claim 2 wherein: Ar and Rare as defined in claim 2; R₁ is chosen from hydrogen, halogen, hydroxy,cyano, nitro, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl) C₁-C₄alkyl, mono- and di-amino(C₁-C₆)alkyl, and—S(O)_(n)(C₁-C₆)alkyl; R₂ is C₃₋₆alkoxy, C₃₋₆cycloalkylalkoxy, NHR_(C),NR_(C)R_(D), or Y; R₃ is hydrogen; R_(A) is independently selected ateach occurrence from halogen, cyano, nitro, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, hydroxy, amino, C₁-C₆alkyl substituted with 0-2R_(B), C₂-C₆alkenyl substituted with 0-2 R_(B), C₂-C₆alkynyl substitutedwith 0-2 R_(B), C₃-C₇Cycloalkyl substituted with 0-2 R_(B),(C₃-C₇cycloalkyl) C₁-C₄alkyl substituted with 0-2 R_(B), C₁-C₆alkoxysubstituted with 0-2 R_(B), —NH(C₁-C₆alkyl) substituted with 0-2 R_(B),—N(C₁-C₆alkyl)(C₁-C₆alkyl) of which each C₁-C₆alkyl is independentlysubstituted with 0-2 R_(B), —XR_(C), and Y; R_(B) is independentlyselected at each occurrence from the group consisting of: i) halogen,hydroxy, cyano, amino, C₁-C₄alkyl, —O(C₁-C₄alkyl), —NH(C₁-C₄alkyl),—N(C₁-C₄alkyl)(C₁-C₄alkyl), —S(O)_(n)(alkyl), halo(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy, CO(C₁-C₄alkyl), CONH(C₁-C₄alkyl), CON(C₁-C₄alkyl)(C₁-C₄alkyl), —XR_(C), and ii) morpholino, pyrrolidino, piperidino,thiomorpholino, and piperazino, each of which is optionally substitutedwith up to three substituents independently chosen from hydroxy,halogen, alkyl and alkoxy; R_(C) and R_(D), which may be the same ordifferent, are independently selected at each occurrence from: hydrogen,and straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkylgroups, said straight, branched, and cyclic alkyl groups, and(cycloalkyl)alkyl groups consist of 1 to 8 carbon atoms, and containzero or one or more double or triple bonds, each of which 1 to 8 carbonatoms may be further substituted with one or more substituent(s)independently selected from oxo, hydroxy, halogen, cyano, amino,C₁-C₆alkoxy, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)(C₁-C₆alkyl),—NHC(═O)(C₁-C₆alkyl), —N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl),—NHS(O)_(n)(C₁-C₆alkyl), —S(O)_(n)(C₁-C₆alkyl), —S(O)_(n)NH(C₁-C₆alkyl),—S(O)_(n)N(C₁-C₆alkyl)(C₁-C₆alkyl), and Z; X is independently selectedat each occurrence from the group consisting of —CH₂—, —CHR_(D)—, —O—,—C(═O)—, —C(═O)O—, —S(O)_(n)—, —NH—, —NR_(D)—, —C(═O)NH—, —C(═O)NR_(D)—,—S(O)_(n)NH—, —S(O)_(n)NR_(D)—, —OC(═S)S—, —NHC(═O)—, —NR_(D)C(═O)—,—NHS(O)_(n)—, —OSiH₂—, —OSiH(C₁-C₄alkyl)-,—OSi(C₁-C₄alkyl)(C₁-C₄alkyl)-, and —NR_(D)S(O)_(n)—; Y and Z areindependently selected at each occurrence from: 3- to 7-memberedcarbocyclic or heterocyclic groups which are saturated, unsaturated, oraromatic, which may be further substituted with one or more substituentsindependently selected from halogen, oxo, hydroxy, amino, cyano,C₁-C₄alkyl, —O(C₁C₄alkyl), —NH(C₁C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl),and —S(O)_(n)(alkyl), wherein said 3- to 7-membered heterocyclic groupscontain one or more heteroatom(s) independently selected from N, O, andS, with the point of attachment being either carbon or nitrogen; and nis independently selected at each occurrence from 0, 1, and 2; providedthat R₁ is not hydrogen, alkyl, or trifluoromethyl when R₂ is hydrogen,alkyl or alkenyl.
 4. A compound or salt according to claim 3 wherein: Ris absent; Ar is chosen from phenyl, naphthyl, pyridyl, pyrimidinyl,pyrazinyl, pyridizinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl,pyrrolyl, furanyl, and triazolyl, each of which is optionallysubstituted with up to 5 independently chosen groups R_(A), wherein atleast one position of said phenyl that is ortho or para to the point ofattachment of Ar in Formula I is substituted.
 5. A compound or saltaccording to claim 3, wherein R is absent; Ar is chosen from phenyl,naphthyl, and pyridyl, each of which is substituted with from 1 to 5independently chosen groups R_(A), wherein at least one position of Arthat is ortho or para to the point of attachment of Ar in Formula I issubstituted.
 6. A compound or salt according to claim 3, wherein R isabsent; Ar is phenyl substituted with from 1 to 5 independently chosengroups R_(A), wherein at least one position of Ar that is ortho or parato the point of attachment of Ar in Formula I is substituted.
 7. Acompound or salt according to claim 3, wherein R is absent; Ar is phenylsubstituted with from 1 to 5 independently chosen groups R_(A), whereinat least one position of Ar that is ortho or para to the point ofattachment of Ar in Formula I is substituted; R₁ is selected fromhydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, halo(C₁-C₂)alkyl, andhalo(C₁-C₂)alkoxy; and R₃ is hydrogen.
 8. A compound or salt accordingto claim 3, wherein R is absent; Ar is phenyl substituted with from 1 to5 independently chosen groups R_(A), wherein at least one position of Arthat is ortho or para to the point of attachment of Ar in Formula I issubstituted; and R_(C) and R_(D), which may be the same or different,are independently selected at each occurrence from: hydrogen, andstraight, branched, and cyclic alkyl groups, and (cycloalkyl)alkylgroups, said straight, branched, and cyclic alkyl groups, and(cycloalkyl)alkyl groups consist of 1 to 8 carbon atoms, and containzero or one or more double or triple bonds.
 9. A compound or saltaccording to claim 3, wherein R is absent; Ar is phenyl substituted withfrom 1 to 5 independently chosen groups R_(A), wherein at least oneposition of Ar that is ortho or para to the point of attachment of Ar inFormula I is substituted; R₁ is selected from hydrogen, halogen,C₁-C₄alkyl, C₁-C₄alkoxy, halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; R₃ ishydrogen; R_(C) and R_(D), which may be the same or different, areindependently selected at each occurrence from: hydrogen, and straight,branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, saidstraight, branched, and cyclic alkyl groups, and (cycloalkyl)alkylgroups consist of 1 to 8 carbon atoms, and contain zero or one or moredouble or triple bonds.
 10. A compound or salt according to claim 3, ofFormula II

wherein: R_(X) and R_(Y) are independently chosen from hydrogen,C₁-C₆alkyl₁, (C₃-C₇cycloalkyl₂)C₁-C₄alkyll, and mono- anddi(C₁-C₆)alkyliamino; where each alkyl₁ is independently straight,branched, or cyclic, contains zero or I or more double or triple bonds,and is optionally substituted with one or more substituentsindependently chosen from halogen, hydroxy, amino, oxo, cyano,C₁-C₄alkoxy, and mono- and di(C₁-C₄)alkylamino, where eachC₃-C₇cycloalkyl₂ is optionally substituted by one or more substituentsindependently chosen from halogen, amino, hydroxy, oxo, cyano,C₁-C₄alkoxy, and mono- or di(C₁-C₄)alkylamino, and R₁, R₃ and Ar are asdefined in claim
 3. 11. A compound or salt according to claim 3, ofFormula II

wherein: R_(X) and R_(Y) are the same or different and are independentlyselected from hydrogen or straight, branched or cyclic alkyl groups,optionally containing one or more aza or oxa bridge, and optionallycontaining one or more double or triple bonds; and R₁, R₃ and Ar are asdefined in claim
 3. 12. A compound or salt according to claim 10,wherein: Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl,furanyl, and triazolyl, each of which is optionally substituted with upto 5 independently chosen groups R_(A), wherein at least one position ofsaid phenyl that is ortho or para to the point of attachment of Ar inFormula II is substituted.
 13. A compound or salt according to claim 10,wherein: Ar is chosen from phenyl, naphthyl, and pyridyl, each of whichis substituted with from 1 to 5 independently chosen groups R_(A),wherein at least one position of Ar that is ortho or para to the pointof attachment of Ar in Formula II is substituted.
 14. A compound or saltaccording to claim 10, wherein: Ar is phenyl substituted with from 1 to5 independently chosen groups R_(A), wherein at least one position of Arthat is ortho or para to the point of attachment of Ar in Formula II issubstituted; R₁ is selected from hydrogen, halogen, C₁-C₄alkyl,C₁-C₄alkoxy, halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and R₃ ishydrogen.
 15. A compound or salt according to claim 10, wherein: Ar isphenyl substituted with from 1 to 5 independently chosen groups R_(A),wherein at least one position of Ar that is ortho or para to the pointof attachment of Ar in Formula II is substituted; R₁ is selected fromhydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, halo(C₁-C₂)alkyl, andhalo(C₁-C₂)alkoxy; and R₃ is hydrogen; and R_(C) and R_(D), which may bethe same or different, are independently selected at each occurrencefrom: hydrogen, and straight, branched, and cyclic alkyl groups, and(cycloalkyl)alkyl groups, said straight, branched, and cyclic alkylgroups, and (cycloalkyl)alkyl groups consist of 1 to 8 carbon atoms, andcontain zero or one or more double or triple bonds.
 16. A compound orsalt according to claim 10, wherein: Ar is phenyl substituted with from1 to 3 substituents independently chosen from: halogen, cyano, nitro,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₃-C₇ cycloalkyl,(C₃-C₇cycloalkyl) (C₁-C₄)alkyl, C₁-C₆alkyl substituted with 0-2 R_(B),C₁-C₆alkoxy substituted with 0-2 R_(B), —NH(C₁-C₄alkyl) substituted with0-2 R_(B), —N(C₁-C₄alkyl)( C₁-C₄alkyl) of which each C₁-C₄alkyl isindependently substituted with 0-2 R_(B), wherein at least one positionof Ar that is ortho or para to the point of attachment of Ar in FormulaII is substituted; R_(B) is independently selected at each occurrencefrom the group consisting of: i) halogen, hydroxy, amino, C₁-C₄alkyl,—O(C₁-C₄alkyl), —NH(C₁-C₄alkyl), and —N(C₁-C₄alkyl)(C₁-C₄alkyl), and ii)morpholino, pyrrolidino, piperidino, thiomorpholino, and piperazino; R₁is selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and R₃ is hydrogen.
 17. Acompound or salt according to claim 10, wherein: Ar is phenylsubstituted with from 1 to 3 substituents independently chosen from:halogen, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, hydroxy, amino,C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl) C₁-C₄alkyl, mono anddi(C₁-C₄)alkylamino, C₁-C₆alkyl substituted with 0-2 R_(B), C₁-C₆alkoxysubstituted with 0-2 R_(B), wherein at least one position of Ar that isortho or para to the point of attachment of Ar in Formula II issubstituted; R_(B) is independently selected at each occurrence from thegroup consisting of: i) halogen, hydroxy, amino, C₁-C₄alkyl,—O(C₁-C₄alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl), and ii)morpholino, pyrrolidino, piperidino, thiomorpholino, and piperazino; R₁is selected from hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy,halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and R₃ is hydrogen.
 18. Acompound or salt according to claim 17 of the formula:

wherein R₁, R₃, and Ar are as defined for claim
 17. 19. A compound orsalt according to claim 17 of the formula:

wherein R₁, R₃, and Ar are as defined for claim
 17. 20. A compound orsalt according to claim 17 of the formula:

wherein R₁, R₃, and Ar are as defined for claim
 17. 21. A compound orsalt according to claim 3, of Formula III

wherein: R_(X) is chosen from C₃-C₆alkyl₁,(C₃-C₇cycloalkyl₂)C₁-C₄alkyl₁; where each alkyl₁ is independentlystraight, branched, or cyclic, contains zero or 1 or more double ortriple bonds, and is optionally substituted with one or moresubstituents independently chosen from halogen, hydroxy, amino, oxo,cyano, C₁-C₄alkoxy, and mono- or di(C₁-C₄)alkylamino, where eachC₃-C₇cycloalkyl₂ is optionally substituted by one or more substituentsindependently chosen from halogen, amino, hydroxy, oxo, cyano,C₁-C₄alkoxy, and mono- or di(C₁-C₄)alkylamino, and R₁, R₃ and Ar are asdefined in claim
 3. 22. A compound or salt according to claim 3, ofFormula III

wherein: R_(X) is selected from straight, branched or cyclic alkylgroups, optionally containing one or more aza or oxa bridges andoptionally containing one or more double or triple bonds; and R₁, R₃ andAr are as defined in claim
 3. 23. A compound or salt according to claim21, wherein: Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrrolyl,furanyl, and triazolyl, each of which is optionally substituted with upto 5 independently chosen groups R_(A) wherein at least one position ofsaid phenyl that is ortho or para to the point of attachment of Ar inFormula III is substituted.
 24. A compound or salt according to claim21, wherein: Ar is chosen from phenyl, naphthyl, and pyridyl, each ofwhich is substituted with from 1 to 5 independently chosen groups R_(A),wherein at least one position of Ar that is ortho or para to the pointof attachment of Ar in Formula III is substituted.
 25. A compound orsalt according to claim 21, wherein: Ar is phenyl substituted with from1 to 5 independently chosen groups R_(A), wherein at least one positionof Ar that is ortho or para to the point of attachment of Ar in FormulaIII is substituted; R₁ is selected from hydrogen, halogen, C₁-C₄alkyl,C₁-C₄alkoxy, halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and R₃ ishydrogen.
 26. A compound or salt according to claim 21, wherein: Ar isphenyl substituted with from 1 to 5 independently chosen groups R_(A),wherein at least one position of Ar that is ortho or para to the pointof attachment of Ar in Formula III is substituted; R₁ is selected fromhydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy, halo(C₁-C₂)alkyl, andhalo(C₁-C₂)alkoxy; and R₃ is hydrogen; and R_(C) and R_(D), which may bethe same or different, are independently selected at each occurrencefrom: hydrogen, and straight, branched, and cyclic alkyl groups, and(cycloalkyl)alkyl groups, said straight, branched, and cyclic alkylgroups, and (cycloalkyl)alkyl groups consist of 1 to 8 carbon atoms, andcontain zero or one or more double or triple bonds.
 27. A compound orsalt according to claim 21, wherein: Ar is phenyl substituted with from1 to 3 substituents independently chosen from: halogen, cyano, nitro,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₃-C₇ cycloalkyl,(C₃-C₇cycloalkyl) (C₁-C₄)alkyl, C₁-C₆alkyl substituted with 0-2 R_(B),C₁-C₆alkoxy substituted with 0-2 R_(B), —NH(C₁-C₄alkyl) substituted with0-2 R_(B), —N(C₁-C₄alkyl)( C₁-C₄alkyl) of which each C₁-C₄alkyl isindependently substituted with 0-2 R_(B), wherein at least one positionof Ar that is ortho or para to the point of attachment of Ar in FormulaIII is substituted; R_(B) is independently selected at each occurrencefrom the group consisting of: i) halogen, hydroxy, amino, C₁-C₄alkyl,—O(C₁-C₄alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl), and ii)morpholino, pyrrolidino, piperidino, thiomorpholino, and piperazino; R₁is selected from hydrogen, halogen, C₁-C₄alkyl, C₁-C₄alkoxy,halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and R₃ is hydrogen.
 28. Acompound or salt according to claim 21, wherein: Ar is phenylsubstituted with from 1 to 3 substituents independently chosen from:halogen, halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, hydroxy, amino,C₃-C₇cycloalkyl, (C₃-C₇cycloalkyl) C₁-C₄alkyl, mono anddi(C₁-C₄)alkylamino, C₁-C₆alkyl substituted with 0-2 R_(B), C₁-C₆alkoxysubstituted with 0-2 R_(B), wherein at least one position of Ar that isortho or para to the point of attachment of Ar in Formula III issubstituted; R_(B) is independently selected at each occurrence from thegroup consisting of: i) halogen, hydroxy, amino, C₁-C₄alkyl,—O(C₁-C₄alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄alkyl)(C₁-C₄alkyl), and ii)morpholino, pyrrolidino, piperidino, thiomorpholino, and piperazino; R₁is selected from hydrogen, halogen, C₁-C₂alkyl, C₁-C₂alkoxy,halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and R₃ is hydrogen.
 29. Acompound or salt according to claim 21 of the formula:

wherein R₁, R₃, and Ar are as defined for claim
 28. 30. A compound orsalt according to claim 28 of the formula:

wherein R₁, R₃, and Ar are as defined for claim
 28. 31. A compound orsalt according to claim 3 of the Formula IV:

wherein R₁, R₃, and Ar are as defined in claim 3, R₄ represents up tothree substituents independently chosen from hydrogen, halogen,C₁-C₆alkyl, and C₁-C₆ alkoxy; and q is 0, 1, or
 2. 32. A compound orsalt according to claim 31, wherein: Ar is phenyl substituted with from1 to 3 substituents independently chosen from: halogen,halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, hydroxy, amino, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl) C₁-C₄alkyl, mono and di(C₁-C₄)alkylamino, C₁-C₆alkylsubstituted with 0-2 R_(B), C₁-C₆alkoxy substituted with 0-2 R_(B),wherein at least one position of Ar that is ortho or para to the pointof attachment of Ar in Formula IV is substituted; R_(B) is independentlyselected at each occurrence from the group consisting of: i) halogen,hydroxy, amino, C₁-C₄alkyl, —O(C₁-C₄alkyl), —NH(C₁-C₄alkyl), and—N(C₁-C₄alkyl)(C₁-C₄alkyl), and ii) morpholino, pyrrolidino, piperidino,thiomorpholino, and piperazino; R₁ is selected from hydrogen, halogen,C₁-C₂alkyl, C₁-C₂alkoxy, halo(C₁-C₂)alkyl, and halo(C₁-C₂)alkoxy; and R₃is hydrogen.
 33. A compound or salt according to claim 3 wherein, in astandard in vitro CRF receptor binding assay the compound exhibits anIC₅₀ value for CRF receptors of less than or equal to 1 micromolar.34-36. (canceled)
 37. A compound or salt according to claim 3, whereinin a standard in vitro Na channel functional assay the compound does notshow any detectable Na channel modulatory activity at the p<0.05 levelof significance in a standard parametric test of statisticalsignificance. 38-41. (canceled)
 42. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a compound or saltof claim
 3. 43-44. (canceled)